Nitric Oxide (NO) is a simple molecule consisting of one atom of nitrogen and one of oxygen, making it even simpler than water. Research into the effects of this small but important molecule began in the 1970’s when scientists started to examine why blood vessels relaxed when certain compounds were added. This led to the discovery of NO and its amazing effects in the body, with NO being named the molecule of the year in 1992. In 1998, twenty-some years after this research first began, a Nobel Prize was awarded to these researchers for their breakthrough discoveries regarding NO. Over
Menopausal women searching for safe and effective alternatives to hormone replacement therapy (HRT) will inevitably come across “phytoestrogens”, either in their whole food form or as a concentrated extract in a supplement. But what exactly are phytoestrogens and how do they work in the human body? Are they even safe? Many answers remain unknown to the general public and the literature can offer mixed results as well. Let’s clear up some of the confusion.
The term “phytoestrogen” can literally be translated into “plant estrogen”. In the 1950’s, this estrogenic activity was discovered in plants when researchers investigated the cause of infertility in a specific group of Australian sheep.1 Researchers noticed that these infertile sheep were grazing in pastures of clover, subsequently labeling genistein as the active ingredient and the constituent responsible in clover for having estrogen-like activity. Since this discovery, hundreds of foods have been identified as phytoestrogens, each possessing varying potencies. Soy, hops, flaxseeds, legumes, lentils, chickpeas, beans, alfalfa sprouts and red clover are now commonly known phytoestrogen sources,2 although when it comes to natural health products, their labels will often only list the active phytoestrogenic ingredient from each plant. See Figure 1 for a list of common phytoestrogenic plants, their corresponding Latin names and their most active estrogenic constituents.
Despite the literal translation to “plant estrogen”, it’s important to note that no actual estrogen exists in
It is also very important to recognize that, even though phytoestrogens activate estrogen receptors, they do so in a much weaker manner. Using our on/off switch analogy, phytoestrogens simply turn on fewer switches than true estrogen because they don’t bind strongly enough to the switch.2 This results in similar physiological responses that are much milder.
Lastly, to fully understand the action of phytoestrogens we must recognize that there are two different types of estrogen receptors in the body: alpha-estrogen receptors (ER-α) and beta-estrogen receptors (ER-β). Each receptor is distributed more heavily in certain tissues (for example bone versus breast tissue). This is important because all phytoestrogens are actually “selective estrogen receptor modulators” (SERMs), meaning they affect either the ER-α or ER-β preferentially.2
Research examining the ability of phytoestrogens to alleviate menopausal ailments is positive, yet still mixed. Beneficial results have been shown for improving hot flashes, vaginal dryness, sleep disturbances, cognition and bone density in menopausal women. However, many studies have also shown very little or no effect of phytoestrogens on menopausal symptoms. With this in mind, it’s important to know that there is a tremendous amount of variability in terms of the amount of active ingredient used in each study. Moreover, individual differences in intestinal microflora can further lead to mixed results by altering the ability to break down and use phytoestrogens in the human body.2
Let’s take a closer look at some of the most popular and most potent phytoestrogens:
Hops(Humulus lupulus) can be considered a relatively “new” phytoestrogen as the active estrogenic ingredient, 8-prenylnaringenin (8-PN) was only recognized in 1999.3 While the hops plant is now acknowledged for its ability to influence menopausal symptoms and other conditions of estrogen imbalance, traditionally hops has been used for its sedative properties.3
Comparison against the active ingredients found in other phytoestrogens (such as genistein and daidzein from soy) show that 8-PN is actually one of the most potent!3 Moreover, 8-PN actually binds ER-α stronger than it binds ER-β, a quite unique property when comparing phytoestrogenic activities.1 Perhaps this partially explains why hops has shown such positive research for menopausal concerns.
Two clinical studies using standardized hops extracts have been conducted, both of which elucidated the rapid and effective relief of hot flashes. One study examined the effects of supplemental hops for 12 weeks in 67 menopausal women while the most recent study in 2010 only examined 36 menopausal women, but over a longer duration of 16 weeks. Both studies measured scores on a modified Kupperman Index (an assessment tool to rate the intensity of hot flashes, insomnia, headaches, vaginal dryness etc.) on a patient questionnaire.4
While the relatively small number of participants in each study may be considered a limitation, the various assessment tools all revealing beneficial effects in such a short duration shows great promise for hops as a treatment intervention. Considering the large proportion of menopausal women with sleep disturbances and hot flashes, hops is an ideal ingredient to target this population for its estrogenic and sedative properties.1In addition, 8-PN has been shown to exhibit estrogenic effects on bone metabolism, thereby providing another menopausal benefit by possibly reducing bone loss.4 Nevertheless, more research is needed to fully reveal all of the benefits that hops have to offer for menopausal women.
Soy is one of the most well-known phytoestrogens, the most researched and also the most controversial. Many research studies have found soy (or the active ingredients isolated from soy; see figure 1) to have no benefit over placebo on menopausal hot flashes.5,6 Yet, other studies show great benefit in specific populations. For example, one study found that soy derived isoflavones improved mood and hot flashes in menopausal women with high body mass index (BMI) measurements.7Another study found that genistein decreased all severities of hot flashes in women entering menopause within the past 12 months with higher BMI’s.8 A 2011 report by the North American Menopause Societystates thatsoy-based isoflavones are “modestly effective in relieving menopausal”.9 This statement is significant because the report literally evaluated hundreds of studies using soy supplementation for menopause and found benefit for its use. Specifically, better results were found in whole food consumption and in products that provided high proportions of genistein. 9 To add support to the argument that isoflavone supplementation does play a positive role in alleviating menopausal symptoms, a comprehensive 2013 review evaluating the efficacy of isoflavones, coumestans and lignans found that current research sufficiently concludes that the findings are positive.2Increased dietary soy consumption has also been shown to decrease endometrial and breast cancer risk in observational studies, perhaps making soy a more attractive option for treating menopause. In addition, possible protective effects on the cardiovascular system, cognition and bone health have been suggested, although research in these areas is much farther from being conclusive.9
Of all the known phytoestrogenic plants, flaxseeds contain the highest amount of lignans, the active ingredient responsible for their estrogenic activity. However, lignans must be converted by the bacteria in the human digestive tract in order to become “activated”.2These active metabolites actually help the liver to make sex-hormone binding globulin (SHBG), a hormone that decreases the clearance of circulating estrogens, and the metabolites also act as SERM’s with an affinity for ER-α.2The end result of both of these processes is more estrogen activity in the body.
Almost all trials assessing the effectiveness of flaxseeds or lignans alone in the treatment of hot flashes have produced insignificant effects. To be more specific, research has found quite a large proportion of flax interventions to reduce hot flashes, but the corresponding placebo groups have proven to be so powerful that there is actually very little difference in the efficacy between groups. However, one study examining the use of isoflavones in conjunction with lignans found significant improvements in hot flashes after 12 months. 10This suggests that perhaps a synergistic effect is present between the two phytoestrogens. This is supported by the fact that vaginal atrophy has also shown improvement through the combined use of lignans and flaxseeds.11
Lignans and flaxseeds have shown improvements in the areas of cognition and bone health, while also possibly showing a protective effect against breast cancer.12Specifically, high dietary lignan intake has been associated with better performance in processing capacity, processing speed and executive function,12 while the alpha-linolenic acid (an omega fatty acid) content of flaxseeds are theorized to benefit bone health by decreasing prostaglandin synthesis. 13The suggested protective effect of lignans on breast cancer has only been observed in dietary observational analysis and therefore the proposed benefit is plausible but far from definitive. 2
A major shortcoming of the use of flaxseeds clinically is that there is currently no long-term research evaluating their efficacy as a sole intervention.2 Perhaps studies of duration longer than 12 weeks would ascertain whether flaxseed is indeed beneficial or not in alleviating menopausal symptoms.
Are phytoestrogens safe?
One of the greatest attributes of phytoestrogens is their extremely high safety profile. A literature review in 2010 analyzed twenty years of soy research and found that there were no serious side effects – only a slightly higher incidence of gastrointestinal disturbances (such as gas or bloating) in those consuming higher amounts of dietary soy.2Similarly, there have been studies examining the safety of soy consumption for up to three years in length that failed to expose any serious adverse effects. Research on the use of lignans from flaxseeds, 8-prenylnaringenin from hops and coumestrol from both alfalfa and red clover have all shown comparable safety profiles. 2, 3
Some research has raised concerns surrounding the use of soy and its possible negative effects on thyroid health.14 It’s important to clarify that: research has only shown that genistein from soy can exacerbate low thyroid function in individuals with pre- existing suboptimal thyroid function (specifically deficient in iodine).14There is currently no evidence to suggest that healthy people consuming soy are at increased risk for hypothyroidism.
As aforementioned, HRT has also raised various concerns regarding their use and possible risk of increased blood clotting, liver disease and certain cancers. Interestingly, phytoestrogens have been found to decrease the risk of endometrial cancer, but also some studies actually suggest a possible protective effect for this type of cancer.2,9Also, soy consumption has actually been found in many human populations to be protective against breast cancer. 2,9
All in all, phytoestrogens appear to be a very safe substitute for HRT that can alleviate women’s health concerns and aid their transition into menopause. Still, to be cautious, it is advised to only utilize phytoestrogens for shorter-term use and at reasonable dosages, as long-term use over a period of years of high-potency extracts have not been explicitly studied.
In summary, there are many different phytoestrogens, in varying capacities, that have shown to be beneficial for
However, as the mixed evidence suggests, each phytoestrogen doesn’t necessarily work for everyone – it’s clear that the type and potency of phytoestrogen
1. Chadwick L et al. The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties. Phytomedicine 2006;13:119- 131.
2. Bedell S et al. The pros and cons of plant estrogens for menopause. J Steroid Biochem Mol Biol. 2013.
3. Erkkola R et al. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine 2010;17:389-396.
4. Heyerick A et al. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2006;54: 164-175.
5. Levis S et al. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med. 2011;171(15):1363-9.
6. St Germain A et al. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause. 2001;8(1):17-26.
7. Chedraui P et al. The effect of soy-derived isoflavones over hot flashes, menopausal symptoms and mood in climacteric women with increased body mass index. Gynecol Endocrinol. 2011;27(5):307-13.
8. Ferrari A. Soy extract phytoestrogens with high dose of isoflavones for menopausal symptoms. J Obstet Gynaecol Res. 2009;35(6):1083-90.
9. Clarkson BT et al. The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H Utian Translational Science Symposium in Chicago, IL. Menopause: The Journal of the North American Menopause Society. 2011;18(7): 732-753.
10. Yoles I et al. Efficacy and safety of standard versus low-dose Femarelle (DT56a) for the treatment of menopausal symptoms. Clinical and Experimental Obstetrics and Gynecology 2004;31(2):123–126.
11. Nachtigall M et al. A prospective study of DT56a (Femarelle) for the treatment of postmenopausal vaginal atrophy, Menopause 2011;18(12):1365.
12. Kreijkamp-Kaspers S et al. Dietary phytoestrogen intake and cognitive function in older women. Journals of Gerontology A: Biological Sciences and Medical Sciences 2007:62(5); 556–562.
13. Kim Y and Ilich JZ. Implications of dietary a-linolenic acid in bone health. Nutrition 2011:27(11–12);1101–1107.
14. Marini H et al. Update on genistein and thyroid: an overall message of safety. Front Endocrinol (Lausanne). 2012;3:94.