The Use of Herbs and Dietary Supplements in Gynecology: An Evidence-Based Review

Cathi E. Dennehy, PharmD

Disclosures

J Midwifery Womens Health. 2006;51(6):402-409. 

In This Article

Methods

A PubMed search was performed in August 2005 by using the search terms "herb" or "supplement" in conjunction with the key words "women," "menopause," "premenstrual syndrome," "dysmenorrhea," "mastalgia," "fertility," and "infertility." Additional PubMed searches were performed by using the name of herbs (including the scientific name) and supplements that were identified. Bibliographies of articles were also searched for other pertinent references.

Black Cohosh (Cimicifuga Racemosa). Black cohosh is widely used for the relief of menopausal symptoms (e.g., hot flashes, insomnia, sweating, and mood changes) and is approved by the Commission E for menopause, PMS, and dysmenorrhea; however, there are no RCTs to support the latter two indications.[4] The most commonly studied preparation, Remifemin, is formulated as an isopropanolic aqueous extract and as a tablet in the United States.[4] This product is standardized by its content of triterpene glycosides, specifically 27-deoxyactein. Each 20-mg tablet contains 1 mg of 27-deoxyactein; the product is typically dosed twice daily.[4]

The mechanism of action of black cohosh is poorly understood. Early trials suggested that black cohosh reduced leutinizing hormone (LH) levels, which have been linked to hot flashes.[5] Older trials suggested that black cohosh had estrogenic properties, as evidenced by proliferation of vaginal epithelium at doses of 80 mg per day (twice the currently recommended dose).[5] Newer trials examined doses of 39 to 127 mg per day for up to 6 months and failed to show effects on hormonal markers, such as LH, follicle-stimulating hormone, prolactin, estradiol, or vaginotrophic, and uterotrophic effects.[6] Agonist properties at serotonin, particularly the 5HT7 receptor and dopamine (D-2) receptors, indicate a possible central role.[7,8] Selective estrogenic properties have also been observed on bone in rats with some protective effects and a lack of proliferative effects in estrogen-sensitive breast cancer cells (MCF-7) in vitro.[9,10] Safety cannot be ensured, as mice that were bred to be prone to developing breast cancer and then fed the daily equivalent of 40 mg of black cohosh were more likely to have metastasis to the lung.[11] Thus, women with a history of estrogen-dependent cancers should avoid this product until risks of use are better defined.

A majority of controlled trials indicate a possible role for black cohosh in alleviating menopausal symptoms, such as hot flashes, vaginal atrophy, and psychological symptoms (e.g., depressive mood, nervousness, and irritability).[5,12,13,14] In comparative trials, the efficacy of black cohosh was similar to 0.625 mg conjugated estrogens (Premarin) and 25 mcg of transdermal estradiol (Estraderm) in alleviating menopausal symptoms over a 3-month period.[12,13] The safety and efficacy of black cohosh in breast cancer survivors is still in question. One controlled trial showed no benefit of adding black cohosh to tamoxifen therapy, compared with placebo and tamoxifen, over a 2-month period.[15] A second trial with an open study design reported no significant benefits of adding 40 mg of black cohosh to tamoxifen at 6 months, but at 1 year, 47% of women in the combination group were hot flash free compared with none of the women in the tamoxifen-only group.[16]

Side effects of black cohosh are rare but may include stomach upset.[17] Of concern are some case reports of hepatotoxicity.[17] Recent RCTs failed to show an effect of black cohosh 40 mg/day on liver enzymes over a 3-month duration.[12,13] Because older clinical trials using higher doses of black cohosh indicate a possible vaginotrophic effect, women who use this product should receive regular gynecologic checkups, and women with estrogen-dependent cancers should avoid its use. The German Commission E recommends limiting use of this herb to 6 months because of a lack of long-term safety data.[4] Black cohosh has no reported drug interactions, but some recent studies indicate a possible inhibitory effect of the herb on Cytochrome 3A4 and 2D6.[18,19]

Phytoestrogens. Phytoestrogens are plant-based compounds that have a greater affinity for estrogen receptor beta than estrogren receptor alpha and are weakly potent compared with estradiol.[20] Phytoestrogens are grouped into four main categories: isoflavones, coumestans, lignans, and flavonoids.[20] The most widely studied group are the isoflavones, consisting of genistein, daidzein, and glycitein.[20] Soybeans are a rich source of isoflavones, and flaxseed is a source of lignans.[20] Flaxseed should not be confused with flaxseed oil, which is a source of omega-3 fatty acids, not phytoestrogens.[21] Red clover (Trifolium pretense) contains compounds that are metabolized to genistein and daidzein after consumption.[20] The most widely studied red clover product is Promensil. Although epidemiologic data suggested that frequent consumption of soy may reduce the incidence of menopausal symptoms,[20] a recent systematic review of the literature concluded no clear benefit of soy foods, soy extracts, or red clover extracts on hot flashes and other menopausal symptoms.[22] This review included RCTs of phytoestrogen foods, beverages, and powders (N = 11), soy extracts (N = 9), and red clover extracts (N = 5), performed through March 2004. Persons who want to consume phytoestrogens should use food products versus supplements and take no more than 100 mg of isoflavones per day, which is equivalent to 25 g of soy protein.[20] The long-term use of high amounts of phytoestrogens is not recommended. One RCT demonstrated a significant increase in the incidence of endometrial hyperplasia (3.8% versus 0%; P < .05) in 179 women who consumed 150 mg/day of isoflavones for 5 years, compared with 187 who consumed placebo.[23] The safety of phytoestrogen use in women with a history of estrogen-dependent cancers is unknown.

Supplements, St. John's Wort, and Kava Kava. Other supplements that have been recommended for reducing menopausal symptoms include evening primrose oil (Oenothera biennis), dong quai (Angelica sinensis), Panax ginseng, wild yam (Dioscorea villosa), and vitamin E. RCTs assessing the herbs in this list have failed to show a clear benefit.[24,25] Vitamin E was associated with a small but significant reduction in hot flashes (one less per day; P ≤ .05) in breast cancer survivors taking 800 IU/day for 1 month, compared with placebo.[25]

Preliminary trials indicate that St. John's wort and kava kava may be beneficial in relieving some of the psychological symptoms associated with menopause. St. John's wort may reduce symptoms of mild to moderate depression, whereas kava kava may benefit symptoms of mild to moderate anxiety.[24,26] St. John's wort has the potential to induce the metabolism of many medications and should be used cautiously in women taking prescription medications.[21] This herb is also known for its ability to cause photosensitivity and may contribute to oxidation of lens proteins in the eye and cataract formation.[21] Persons using St. John's wort should be monitored for symptoms of agitation, insomnia, hypomania, and mania, which have occurred in rare instances, and should wear sunglasses and sunscreen when outdoors.[21] St. John's wort should not be used in conjunction with other medications, which have the potential to increase endogenous norepinephrine, dopamine, or serotonin levels (e.g., antidepressants), as additive adverse effects, such as serotonin syndrome, may occur.[21]

Although kava kava has shown benefits in alleviating anxiety associated with menopause, it may also have a damaging effect on the liver and was removed from the market of many European countries because of this side effect.[27] Use of this product is not recommended in persons with preexisting liver disease or who consume other chemicals (e.g., acetaminophen or alcohol) that can damage the liver. The German Commission E recommends limiting use to no more than 3 months without medical advice.[4] Persons using kava should also have liver function tests performed periodically. It should never be used in conjunction with other medications that can impair coordination or cause central nervous system sedation, because ataxia and motor impairment have been observed.[21] Finally, kava has been associated with case reports of extrapyramidal reactions and should be avoided in persons with a history of Parkinson's disease.[21]

Dysmenorrhea is a common symptom among young women and a leading cause of absenteeism from work and school.[28] Primary dysmenorrhea is caused by the release of prostaglandins, primarily PGE2 and PGF2, which cause inflammation, pain, and spastic uterine contractions.[29] Secondary dysmenorrhea may be related to endometriosis, which is caused by a defect in retrograde menstruation, resulting in the implantation of endometrial tissue in pelvic and other extrauterine areas, causing pain, uterine bleeding, and infertility.[28,29]

Many herbs and dietary supplements have been proposed as being effective for primary and secondary dysmenorrhea, including black cohosh, chastetree, dong quai, black haw (Virburnum prunifolium), crampbark (Viburnum opulus), omega-3 fatty acids, vitamin E, thiamine (vitamin B1), niacin (vitamin B3), and magnesium.[28,30] All of the herbs in this list lack RCTs to support their use, but some (black haw and crampbark) have animal data indicating a uterine relaxant effect, which could be beneficial in humans.[21,30] Black haw contains oxalic acid and should not be used in women with a history of kidney stones.[21] Evidence-based support for niacin is weak. One open trial conducted in the 1950s suggested an improvement in menstrual cramps in 90% of women who took 100 mg of niacin twice daily and every 2 to 3 hours during cramping.[31] This dosing frequency, in addition to the fact that niacin can cause flushing, make it a less than optimal choice.[31] A Cochrane review of herbs and supplements for primary and secondary dysmenorrhea concluded that vitamin B1 was promising, as was preliminary evidence for magnesium.[28] Another systematic review concluded that fish oil was promising.[32] Vitamin E has also been the subject of a large new RCT showing symptomatic relief.[33] Studies involving these four therapies are reviewed below.

Thiamine (Vitamin B1). The single largest RCT to date involving an herb or supplement for dysmenorrhea evaluated thiamine.[34] The trial was conducted in 556 young (aged 12-21) women living in India with moderate to very severe symptoms. Women received placebo for 2 months or 100 mg of thiamine per day for 3 months in a crossover study design. At the end of the study, symptomatic improvement with thiamine was greater than 90%, compared to less than 1% for placebo. It is unclear if this strong beneficial response would also be observed in American women, whose genetics, diet, and culture are different. The low placebo response also casts some doubt on the validity of these findings.

Vitamin E. Vitamin E has been studied in three RCTs.[33,35,36] Its mechanism of action is unclear but may involve a reduction in prostaglandin formation by inhibiting arachidonic acid release.[33] Two smaller trials, both involving 100 adolescent women, showed a significant reduction in pain when vitamin E 150 to 500 IU/day was administered a few days before and during menses compared with placebo for two to three cycles.[35,36] The most recent trial involved 278 women, aged 15 to 17, who received 400 IU/day vitamin E or placebo 2 days before and 3 days during menses for four cycles.[33] Pain severity, pain duration, and blood loss were significantly lessened (P < .001) in the vitamin E group at 2 and 4 months (P < .001). Two of the three trials were conducted by using a sample of women living in Iran; it is unclear if these benefits would also be observed in women who live in other areas.[33,36] Because vitamin E can have antiplatelet properties, it should be used cautiously in women who are on anticoagulants.[21] Recent evidence suggests that high-dose vitamin E (greater than 400 IU/day) may contribute to a slight increase in mortality and heart failure. Thus, daily intake should be limited to 400 IU or less, even though an estimated 11.3% of Americans supplement with doses of vitamin E that are at least 400 IU/day.[37] Vitamin E is available as a synthetic (d-l-alpha-tocopherol, also referred to as alpha-tocopherol or SRR-tocopherol) or natural (d-alpha tocopherol or RRR-tocopherol) formulation. The natural formulation is more bioavailable and, thus, greater in potency by a ratio of 1.36 to 2:1.[38] Therefore, 400 IU of natural vitamin E is not equivalent to 400 IU of synthetic vitamin E. Effects would be equivalent if dosing were proportionally adjusted on the basis of bioavailability.

Magnesium. Magnesium has been studied in three small RCTs, with sample sizes of 21 to 50 women.[28] Two trials reported significant improvements in pain, but both of these had withdrawal rates of greater than 30%.[28] Formulations of magnesium, method of administration, and therapy duration varied in each trial. As such, these findings offer limited support for a role of magnesium in alleviating symptoms of dysmenorrhea.

Omega-3 Fatty Acids. Americans have diets that are rich in omega-6 fatty acids (e.g., vegetable oil, eggs, and margarine) and poor in omega-3 fatty acids (e.g., fish, canola oil, and wheat germ).[39] Omega-6 fatty acids contribute to the formation of proinflammatory eicasanoids, such as PGE2, thromboxane A2, and leukotriene B4, whereas omega-3 fatty acids, mainly eicosapentanoic acid and docosahexanoic acid, lead to the formation of less inflammatory eicasanoids (e.g., PGE3, thromboxane A3, and leukotriene B5).[39] There is some epidemiologic evidence that a diet rich in omega-3 fatty acids can decrease painful menses.[39] One small RCT involving 42 adolescent women demonstrated a significant decrease in menstrual pain and need for ibuprofen in those using fish oil (1.8 g of eicosapentanoic acid and docosahexanoic acid per day) for 2 months versus placebo (P < .004).[28] An increased intake of fish oil in amounts of 1 to 2 g/day is also likely to benefit cardiovascular risk factors such as elevated triglycerides.[39] Because omega-3 fatty acids have antiplatelet properties, they should be used cautiously in persons taking anticoagulants.[21] Omega-3 fatty acids have few side effects, but they may cause bad breath, stomach upset, and loose stools.[21] The commercial stability of fish oil preparations can vary markedly, from 1 to 200 days, depending on susceptibility to lipid peroxidation.[39] Unfortunately, vitamin E, which is added to fish oil preparations to decrease oxidation, does not seem to impact this stability.[39] Once opened, most preparations will only be stable for 10 to 14 days.[39] As such, it is better to increase dietary intake of fish rather than taking supplements.

As many as 85% to 90% of premenopausal women experience regular premenstrual symptoms consisting of changes in mood (e.g., depression and irritability), water retention, fatigue, breast tenderness, and dysmenorrhea.[40] Breast tenderness, or mastalgia, can be either cyclic (associated with menstruation) or noncyclic. Cyclic mastalgia is more common (67% of cases), is easier to treat,[41] and is discussed here. The majority of RCTs investigating dietary supplements in treating PMS have evaluated vitamin B6.[32] The use of chasteberry for treating cyclic mastalgia has been supported.[42,43,44] Calcium has also been studied.[40] Evening primrose oil (Oenothera biennis), which is commonly marketed for alleviating symptoms of PMS and breast pain, has generally not shown a significant benefit.[32] Efamast, a popular product used to treat mastalgia in the United Kingdom, recently had its license withdrawn by the Medicines Control Agency because of a lack of sufficient proof of efficacy.[45] Given this, and the negative findings of the largest and most recent RCT involving evening primrose oil for cyclic mastalgia, it cannot be recommended for this indication at this time.[46]

Calcium for PMS. Three studies indicate an inverse relationship between calcium intake and the development of PMS symptoms.[40] A nested case-control study within the prospective Nurses' Health Study cohort found that intake of calcium from foods, but not supplements, was inversely associated with PMS symptoms, with women in the highest intake group (average of 1283 mg/day) having the lowest relative risk (RR) (0.70, 95% CI 0.50-0.97). The RR for women who consumed any type of milk frequently (two or more servings per day) was 0.70 (95% CI 0.55-0.90). Women who consumed whole milk more than once a week had a slight increase in the risk of developing PMS (RR 1.31; 95% CI 0.91-1.87), whereas those who consumed skim or low fat milk two to three times per day or four or more times per day had the lowest risk (RR 0.66; 95% CI 0.52-0.83; and RR 0.54; 95% CI 0.32-0.91, respectively).

Although this case-control study found no correlation with calcium supplement intake and a reduction in symptoms of PMS, two RCTs suggest otherwise.[32] Both trials used 1000-1200 mg of elemental calcium (from calcium carbonate) daily for three cycles and observed an approximate 50% reduction in symptom scores, compared to a 20% to 30% reduction for placebo. The mechanism of action for calcium in PMS is unclear but may be tied to hormonal fluctuations in estradiol during ovulation and the luteal phase.[40] Because calcium is relatively free of side effects, it is an attractive option for women suffering from PMS.

Vitamin B6 in PMS. The use of vitamin B6 in PMS was recently included as part of an overall review of complementary and alternative medicine therapies in women.[32] Among the 14 RCTs that were included, 5 observed no benefit, 2 observed some benefit in emotional or autonomic and behavioral symptoms, and 7 observed significant improvements. Vitamin B6 was typically given in daily doses ranging from 50 to 500 mg. A majority of these trials were conducted in the 1980s, with the most recent in 1991; more recent trials examining the efficacy of vitamin B6 are warranted. Vitamin B6 has been a popular therapy in Europe. However, a survey of general practitioners in the United Kingdom revealed that vitamin B6 accounted for 22% of prescriptions for PMS in 1993, but only 11% in 1997 and 1998. With the use of serotonin reuptake inhibitors for PMS, vitamin B6 may not be being used as frequently as in the past.[47] It is not clear why vitamin B6 may be beneficial, but it has been hypothesized that women suffering from PMS might be deficient in vitamin B6.[32] Given the benign nature of vitamin B6 in these dosages, it is also an attractive option for PMS.

Chasteberry (Vitex Agnus Castus) in PMS and Mastalgia. The German Commission E approved chasteberry for the treatment of PMS and mastalgia.[4] Some women with PMS and breast pain have elevated prolactin levels.[48] Chasteberry inhibits prolactin release through dopamine (D-2) receptor stimulation.[48] Chasteberry has been the subject of three RCTs for cyclic mastalgia and four for PMS.[32,42,43,44,49,50]

For cyclic mastalgia, chasteberry has demonstrated significant benefits over placebo with daily use for 2 to 3 months.[42,43,44] All of these trials used a combination preparation known as Mastodynon, which contains chasteberry in addition to other herbs (Caulophyllum thalictroides, Cyclamen, Ignatia, Iris, and Lilium tigrinum) and is not available in the United States.[42] Only one of the studies was published in English,[42] whereas the other two provided English abstracts but were published in German[43] and French.[44] The English language trial evaluated 100 women who received Mastodynon 60 drops/day (daily equivalent of 32.4 mg chasteberry extract) for 3 months. Pain was evaluated by using a visual analog scale. At 1 and 2 months, chasteberry was significantly better than placebo at reducing pain (P = .018 and P = .006, respectively). At 3 months, these differences were only of borderline significance (P = .064). The abstract for the German language study did not provide dosing details, but it indicated that 104 women received either Mastodynon solution (n = 34), tablets (n = 32), or placebo (n = 38). Pain, as measured by visual analog scale, was significantly improved in both chasteberry groups compared with placebo at 3 months (P = .007 for solution; P = .008 for tablets). The abstract for the French language study also did not provide dosing details, but it indicated that 160 women received a progestagen (lynestrenol), Mastodynon, or placebo. Significant relief was observed in 82.1% of patients taking lynestrenol, 74.5% taking Mastodynon, and 36.8% taking placebo.

For PMS, chasteberry has been evaluated in four RCTs. Chasteberry showed no benefit over placebo in one trial,[49] a significant benefit over placebo in another trial,[32] and equivalent efficacy to vitamin B6[32] and fluoxetine[50] in two controlled, comparative trials. It is important to recognize that unlike fluoxetine, vitamin B6 is not considered a proven remedy for PMS, so proof of equal effectiveness is not as meaningful. All of these trials used different doses of chasteberry and lasted 2 to 3 months.

In the placebo-controlled trial, which observed no benefit, 1800 mg/day of powdered chasteberry was used. The trial involved 217 women and lasted for 3 months.[49] The other placebo-controlled trial involved 178 women (170 completed the trial) and used 20 mg of a standardized chasteberry extract known as Ze 440.[32] At 3 months, all symptoms (irritability, mood alteration, anger, headache, and breast fullness) except bloating were significantly improved (P = .001) compared with placebo.

In the comparative trial with vitamin B6, 175 women were randomized to receive 200 mg of vitamin B6 or 3.5 to 4.2 mg of Agnolyt, a dried chasteberry extract, for 3 months.[32] Both groups showed significant reductions in PMS symptom scores (P < .05), but the chasteberry group had more marked symptom alleviation than the vitamin B6 group (77.1% improvement versus 60.6%, P < .05, respectively). In the other comparative trial, 41 women with premenstrual dysphoric disorder were randomized to receive 20 to 40 mg of fluoxetine (Prozac) or 20 to 40 mg of chasteberry extract (Ze 440).[50] In this 2-month, single-blind trial, clinical improvement was defined as follows: 1) premenstrual dysphoric disorder criteria no longer being met (as defined by the Diagnostic and Statistical Manual of Mental Disorders-IV), 2) having "much" or "very much" improved clinical global impression scale-severity of improvement, 3) a 50% decrease in Hamilton depression rating scale, 4) a 50% decrease in daily symptom reports, and 5) agreement of two authors that the patient was sufficiently improved. Based on these criteria, 68.4% of patients in the fluoxetine group improved, compared to 57.9% of patients in the chasteberry group. These differences were not significantly different.

Side effects for chasteberry are characterized as mild and reversible.[51] The most frequent adverse effects were upset stomach, headache, menstrual disorders, acne, itching, and rash. Chasteberry has not been reported to have any major drug interactions. Femaprin (Nature's Way, Springville, Utah) is the US equivalent of Agnolyt.[4] Recommended dosing is 30 to 40 mg/day.[4]

Infertility is associated with endometriosis, luteal phase defects, and reduced fecundity. Oxidative stress can negatively impact oocyte maturation, fertilization, embryo development, and pregnancy, which has led to the use of antioxidants as a possible treatment strategy.[52] High levels of prolactin can also decrease fertility, indicating that chasteberry might also be useful.[48] Few RCTs evaluating dietary supplements for infertility exist. The products that have been studied are free of serious side effects and may warrant consideration.

Vitamin C. One large RCT studied 150 women with luteal phase defects to determine if daily supplementation with 750 mg/day of vitamin C could affect progesterone levels and fertility.[52] After 6 months of treatment, the fertility rate in the vitamin C group was significantly higher than in the placebo group (25% versus 11%, P = .045). Progesterone levels were also significantly increased in the treatment group (52.6% versus 21.7%, P < .01). Beneficial effects may be related to the antioxidant properties of the vitamin and the effects of oxidative stress in oocyte maturation and fertilization.

Chasteberry. Mastodynon, a preparation containing chasteberry and other herbs, was studied in 96 women with secondary amenorrhea, luteal insufficiency, or idiopathic infertility.[53] Women were randomized to receive 30 drops of Mastodynon twice daily or placebo for three cycles. Sixty-six of the 96 women were described as being "suitable for evaluation." Because only the abstract of this article was in English, the rationale for the exclusions could not be determined. Fifteen of the women conceived (seven with amenorrhea, four with idiopathic infertility, and four with luteal insufficiency). Twice as many conceptions occurred among the women with amenorrhea or luteal insufficiency who received Mastodynon.

Fertility Blend. Fertility Blend is a proprietary combination of chasteberry; green tea extracts; L-arginine; vitamins E, B6, and B12; folate; iron magnesium; zinc; and selenium.[54] A pilot study randomly assigned 30 women, aged 24 to 46 who were unsuccessful at conceiving over 6 to 36 months, to receive Fertility Blend, three capsules per day, or placebo for three cycles. At 5 months, significantly more women in the treatment group were pregnant (33% versus 0%, P < .01). Four of the five women had healthy live births, and one had a miscarriage, where implantation on a leiomyoma may have contributed. L-arginine, one of the product's ingredients, may act by improving blood flow to the follicles and uterus. L-arginine was also studied as a supplement in women undergoing in vitro fertilization and was found to be detrimental to embryo quality and pregnancy rate compared with in vitro fertilization and placebo.[55]

Gynecologic symptoms, which are often chronic in nature, may be self-treated with herbs and dietary supplements. Midwives should be aware of which therapies have evidence-based support, carry a low side effect burden, and the least potential to interact with other medications.

It is important to use evidence-based resources when seeking information about herb and supplement products. The Natural Medicines Comprehensive Database is one such source.[21] Independent testing laboratories, such as Consumer Lab and the United States Pharmacopoeia, can be used to determine reputable manufacturers. Consumer Lab independently checks a random sample of a manufacturer's products to verify product content.[56] Access to their database requires a small yearly fee. Manufacturers can also pay a fee to have their products tested by the United States Pharmacopoeia. If a supplement carries a United States Pharmacopoeia verification symbol on its label, it has been evaluated for product content, good manufacturing practices, product dissolution in the human body, and lack of contaminants.[1]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....