Opportunities abound for botanicals suppliers to market plant-based hormone regulators of interest to menopausal women. Christopher Hobbs unearths those botanicals with promise — and those without
Opportunities abound for botanicals suppliers to market plant-based hormone regulators of interest to menopausal women. Christopher Hobbs unearths those botanicals with promise — and those without
Oestrogen connotes youthfulness and sexuality, but on the other side of the coin lies cancer and heart disease. Thousands of research studies have provided sometimes conflicting results, yet many questions have been significantly answered. Yes, oestrogen does increase a woman?s risk of breast cancer and uterine cancer. No, it does not increase cervical cancer risk. Yes, it does reduce hot flashes. And yes, it can help prevent bone loss and osteoporosis after menopause.
Recently, oestrogen-like compounds from plants have received interest from the research community and consumers alike because of their possible benefits to menopause-related conditions. These compounds include soy-based supplements containing isoflavones such as genestein; lignans from flaxseed; and traditional herbs such as black cohosh, vitex, wild yam and red clover.
While these seem mostly safe to add to the diet in foods or dietary supplements, what evidence is available to support their effectiveness for relieving unwanted symptoms that could arise in relation to oestrogen imbalances? At this point, there is only preliminary evidence that fulfils contemporary scientific standards. But, with a careful and considered review of the complete scope of studies on any given aspect of oestrogen?s benefits or potential risks, some clear recommendations are possible.
Many of the troublesome symptoms that women experience — including premenstrual syndrome, irregular menstruation, menstrual cramps and repeated miscarriage — are related to hormones.
During the last decade, medical researchers discovered that an overabundance of oestrogen can increase the risk of even more far-reaching complications: endometriosis, uterine fibroids, cervical dysplasia, breast cysts, endometrial cancer, stroke, pulmonary embolism and breast cancer.1,2,3,4,5
Oestrogen is also responsible for many beneficial physical changes in women. Acting as a neurotransmitter in the brain, oestrogen levels can affect mood and energy. In some women it stimulates the oil glands in the skin and scalp, making their skin and hair softer and silkier. Another benefit of oestrogen is that it discourages wrinkles and acne, keeping skin pliable and toned by promoting the production of collagen, which forms the skin?s basic framework. Oestrogen is also involved in increasing secretions that lubricate the vagina and help maintain vaginal and urinary tract cell renewal and muscle tone.6,7,8
Considering all these facts about oestrogen, what can be said about its benefits and risks? The definitive study that made media headlines around the world was the Women?s Health Initiative (WHI), a major set of clinical trials and an observational study that began in 1991. What made it so definitive is that it included altogether more than 161,000 generally healthy postmenopausal women. Often the effects of a drug or treatment are hard to decipher, based on the many confounding variables present in the daily lives of women today. These include diet, exercise, other medications and the presence of synthetic oestrogen-like chemicals in the environment called xeno-oestrogens.
The WHI reduced the influence of these variables on the outcomes through sheer numbers — with this many women, enough will be eating similar diets, taking the same medications and exposed to the same environmental influences. In other words, the large sample size gives the study outcomes more statistical power.
The WHI study also changed the way doctors prescribe oestrogen in the US — from nearly unbridled promotion to definite caution, almost overnight.
The WHI?s findings
The WHI was designed to test the effects of postmenopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer. The researchers studied large groups of women who were taking oestrogen-plus-progestin, and women on oestrogen alone.9
In the oestrogen-plus-progestin study, women had more heart attacks, strokes, blood clots and breast cancers compared to those taking placebo. These women also had fewer colorectal cancers and hip fractures, but there was no effect on the number of deaths. More recently, the researchers saw increased risk of stroke and decreased risk of fractures with oestrogen alone, but this treatment did not increase breast cancers or decrease colorectal cancers. The data in the oestrogen-alone group is still being analyzed, and no firm recommendations have been made yet.
Another finding concerns the risk of mild or moderate cognitive impairment, including effects on memory and alertness. Oestrogen therapy alone, or in combination with progestin, both increased the risk of dementia and mild cognitive impairment.
The clear benefits to come out of the study were few. As expected, though, some bone protection was noted, though this was not as robust an effect as seen in earlier studies. For 10,000 women who take oestrogen, six fewer women would have hip fractures, and bone mineral density was increased by 3.7 per cent. However, researchers concluded that ?When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.?10
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As herbal prescriptions to alleviate symptoms associated with hormone imbalances date back 2,000 years, scientists began looking into these traditional remedies in earnest beginning in the 1950s. Vitex is an herb whose virtues were extolled around 450 BC, and the first modern extract was produced in Germany about 50 years ago.
Vitex and black cohosh are examples of time-honoured herbs that can change hormone levels in the body by working on the pituitary gland, which controls the ovaries to produce oestrogen and progesterone.11,12 Black cohosh has been found to significantly change levels of luteinizing hormone, which is made in the pituitary gland.
To an herbalist, herbs and herbal formulas are useful for regulating the liver, improving digestion and mood, calming the nervous system, increasing energy, promoting sound sleep, and other beneficial effects to help women through the time of perimenopause. In this article we will focus mainly on herbs that have good scientific support for their use for hormone-related imbalances in women, or herbs that have at least been used traditionally.
According to many herbalists, liver herbs like burdock, dandelion and yellow dock can also regulate hormone levels because it is the liver that is primarily involved with breaking down oestrogen and other hormones when levels get too high. Many commercial formulas designed to relieve the symptoms that occur with PMS, or around the time of menopause, include liver herbs; the same idea is also accepted in traditional Chinese medicine. However, scientific studies to confirm the benefits of this approach are mostly lacking.
Three major categories of herbs (and foods) can affect hormone balance and effectiveness in our body. These categories might overlap somewhat, but it is useful to look at them separately to better understand how herbs and foods can act like hormones and alter hormone balance. We will review herbs and nutrients for the liver, which can also affect hormone balance, later in this section.
Phytosterols or phytosteroids are plant steroids found in foods and herbs that may or may not act as weak hormones in the body. Steroids are fat-soluble molecules that have a basic 17-carbon 4-ring structure called the cyclopenateoperhydro-phenanthrene ring system. Steroids from plants and humans share this common basic structure, but they are not equivalent because of varying chemical groups that attach to the main ring in different positions. These include diosgenin and related compounds in wild yam, sarsaparilla and Tribulus terrestris.
Phytosterols have the same basic molecular ring structure as oestrogen and progesterone, but are different enough so that they are unlikely to act like human steroids in the body. Despite their popularity, animal and human studies have so far been unable to show that products like wild yam cream by themselves have any hormonal effect.
Effective wild yam products often have added progesterone that is produced synthetically from diosgenin, the major phytosterol in all species of wild yam, from the genus Dioscorea. The only clinical trial with wild yam extract (sans progesterone) was performed at the Baker Medical Research Institute in Australia.13 In a double-blind, placebo-controlled, cross-over study, 23 healthy women suffering from hot flashes and other symptoms were either given a wild yam cream to apply topically, or a placebo cream for six months. After three to six months of treatment, no side effects from the cream were reported, but no changes in follicle-stimulating hormone, estradiol or progesterone were seen either. No statistically significant improvement on hot flashes or night sweats was noted in either group.
Phyto-oestrogens are plant constituents that, while not actual steroids or hormones, are well known to interact with oestrogen receptor sites in the body.14 These fall into four categories: isoflavones like genistein from the pea family (especially soy, red clover and kudzu); coumestans like coumestrol from red clover; polyphenols like 8-isopentenylnaringenin from hops; and lignans from flaxseed such as enterodiol and enterolactone.15
Black cohosh contains phyto-oestrogens reported to have a direct oestrogenic effect, but it also has compounds that act as hormone regulators through the pituitary gland, and other as yet unidentified mechanisms.16
Red clover, soy and flax extracts have been shown to have a significant oestrogenic effect in animals and humans. Whether these effects translate into real clinical benefits for reducing hot flashes and protecting bone density remains to be proven with larger and better-designed clinical trials.17 The safety of regular long-term genistein use also has been questioned, but appears to be safe if the dose is kept under 60mg/day.
Hormone regulators are herbs that contain diverse compounds that affect human hormone production by stimulating the pituitary gland or adrenal glands to produce more or less of hormones like oestrogen or progesterone, or regulate the levels of other hormones like luteinizing hormone, prolactin and follicle-stimulating hormone.
These herbs do not contain compounds that act directly on the body?s cells like oestrogen or testosterone, inducing nuclear expression of DNA to produce proteins; rather, their effect on the body?s cells is indirect. The most credible and successful products — vitex and black cohosh — fall into this category. A short review of these two well-documented herbs follows.
This is the most popular native North American herb for hormonal imbalances. Its use goes back centuries as an American Indian remedy for women?s health ailments, and it was adopted in the early 20th century by Western-trained physicians.
Black cohosh standardised extracts in tablets and capsules are increasingly popular as a natural alternative to oestrogen, especially for relieving hot flashes. Research shows that extracts of the underground parts are either oestrogenic or not oestrogenic, depending on the study.18,19 In reviewing a number of these studies, the predominance of them fail to find a direct oestrogenic effect.14,20 Furthermore, it does not stimulate the growth of breast cancer cells in vitro,20 and, in fact, could significantly inhibit breast cell cancer growth in vitro.21 Prolonged use should still probably be avoided by women who have an increased risk of familial breast cancer, or who already have any cancer of the reproductive tract, until we know more about its long-term effects. Notably, reported acute side effects were seen to be mostly mild and reversible in a critical evaluation of studies including 2,800 patients.22
Recent controlled studies in humans have shown black cohosh extracts to exert a positive effect on menopausal symptoms generally,23 and bone metabolism and vaginal cell regeneration specifically, while not increasing endometrial thickening in the uterus,24 as well as helping to relieve hot flashes associated with chemotherapy and menopause,25 and migraines associated with PMS.26
However, as is usually the case with scientific investigation, further studies of good design and that include sufficient numbers of patient volunteers will be needed before black cohosh is accepted as an effective alternative by the medical community. At least one recent study showed no benefit from black cohosh against hot flashes among women with a history of breast cancer.27
This ancient herb is the most credible herbal ingredient for relieving symptoms associated with PMS, especially breast tenderness.28 It has a 2,000 year track record of use by herbalists and a number of positive clinical trials support this ancient use.
Extracts (either tinctures or standardised powders in capsules or tablets) exert their main influence on the pituitary gland and hypothalamus, regulating luteinizing hormone, follicle stimulating hormone, prolactin, progesterone and oestrogen levels, as well as helping to relieve symptoms like PMS (especially breast tenderness), cyclic acne, constipation, and menstrual irregularities such as polymenorrhea and mood swings.28,29,30
For mild depression associated with PMS, vitex worked almost as well as a selective serotonin reuptake inhibitor.31 It is also sometimes recommended in Europe for helping to ease the transition away from birth control pills and for decreasing mood swings during menopause.
It should be noted that vitex does not act like oestrogen in the body. Side effects are minimal — the rare upset stomach and reduced menstrual flow. Many earlier studies have been performed on vitex liquid extracts, some of them controlled and some of them multicentre prospective or retrospective studies that were partially controlled, and some uncontrolled clinical reports are available. Most of these show positive results for reducing breast tenderness, acne, headaches, cramps and other symptoms. (For a review of these studies, see Hobbs, 2003.32)
Soy, red clover, kudzu root
Many members of the pea family, including soy, red clover extracts and kudzu root, contain isoflavones. The major compound is called genistein, which has been the focus of thousands of research articles.
Genistein does activate oestrogen receptors in humans and has a decided oestrogenic effect, though this effect is many times less potent than the human equivalent, estradiol. The compound does not affect cells in the same way as human oestrogen though, and the differences are still being worked out.
Estradiol enters target cells in the body, such as in the breast or uterus, goes to the nucleus, and directly acts as a stimulant of DNA transcription by binding to oestrogen-responsive elements directly on the DNA, increasing transcription of mRNA and subsequently the levels of a number of important proteins that affect cell growth, signalling and differentiation.
Estradiol also affects cells through cell membrane receptors, which are non-genomic effects mediated through complex and multiple signalling pathways in various cells of the body. These interactions are extremely complex and are still being worked out.33 (See Nadal, et al, 2001 for a good review.)
Because genistein is not truly a human oestrogen but simply looks like the molecule to the body because of its similar structure, it cannot be expected to trigger all of these genomic and extra-genomic pathways in exactly the same way. However, it is known that genistein does affect the two nuclear oestrogen receptor sites on DNA — ER-alpha and Er-beta — though not in exactly the same way as estradiol. Specifically, genistein has about a 30 times higher affinity for Er-beta, and about a 50 times weaker effect on Er-beta,34 and does not affect Er-beta-dependent gene expression in the hypothalamus.35
About 60 randomised trials with genistein are available and some show such effects as reduced hot flashes,36 bone resorption37 and blood sugar-regulating effect in postmenopausal women.38 However, many other studies showed no effects.39 Larger and better-designed studies need to be performed to clarify the clinical relevance of the chemical and pharmacological studies performed on this interesting ingredient.
Christopher Hobbs, LAc, AHG, is a botanist, clinical herbalist and licensed acupuncturist, and is currently pursuing a PhD in ethnopharmacology. He has written or co-written 24 books on health and herbs. He is formulator and consultant to Rainbow Light Nutritional Systems, and Secara, a professional line of formulas for practitioners of traditional Chinese medicine. Respond: [email protected] All correspondence will be forwarded to the author.
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2. Cook JD, Walker CL. Treatment strategies for uterine leiomyoma: the role of hormonal modulation. Semin Reprod Med 2004; 22:105-111.
3. Elson DA, et al. Sensitivity of the cervical transformation zone to oestrogen-induced squamous carcinogenesis. Cancer Res 2000; 60:1267-75.
4. Dixon JM. Hormone replacement therapy and the breast. BMJ 2001; 323:1381-2.
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11. Milewicz A, et al. Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study. Arzneimittelforschung 1993; 43(7):752-6.
12. Duker, et al. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med. 1991 Oct; 57(5):420-4.
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23. Liske E et al. Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic oestrogenic effect. J Womens Health Gend Based Med 2002; 11(2):163-74.
24. Wuttke W et al. The Cimicifuga preparation BNO 1055 vs. conjugated oestrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas. 2003 Mar 14; 44 Suppl 1:S67-77.
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28. Halaska M, et al. Treatment of cyclical mastodynia using an extract of Vitex agnus castus: results of a double-blind comparison with a placebo. Ceska Gynekol 1998 Oct; 63(5):388-92.
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30. Lauritzen C. et al. Treatment of premenstrual tension syndrome with Vitex agnus castus. Controlled, double-blind study versus pyridoxine. Phytomedicine 1997; 4(3), 183-89.
31. Atmaca M et al. 2003. Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol 2003; 18(3):191-5.
32. Hobbs CR. Vitex, the Women?s Herb. 2nd edition. Summertown, TN: The Book Publishing Company. 2003.
33. Nadal A, et al. The oestrogen trinity: membrane, cytosolic, and nuclear effects. News Physiol Sci 2001; 16:251-5.
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35. Patisaul HB, et al. Genistein Affects ER?- But Not ER-Dependent Gene Expression in the Hypothalamus. Endocrinology 2002; 143(6):2189-97.
36. Crisafulli, et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebo-controlled study. Menopause 2004 Jul-Aug; 11(4):400-4.
37. Harkness LS, et al. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004 Nov; 13(9):1000-7.
38. Cheng SY et al. The hypoglycemic effects of soy isoflavones on postmenopausal women. J Womens Health (Larchmt) 2004; 13(10):1080-6.
39. Kreijkamp-Kaspers S et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004 Jul 7; 292(1):65-74.