:Phytoestrogens:
Alternatives to HRT

Phytoestrogens are naturally occurring plant sterols, capable of exerting effects similar to estrogen. They can be classified into three groups:

• Isoflavones, most commonly genistein and daidzein, are plant sterol molecules found in soy, garbanzo beans, and other legumes.
• Lignans are components of plant cell walls, and become bioavailable through the metabolism of grains by intestinal bacteria. Seed oils, particularly flax, are rich sources of lignans.
• Coumestans, although extremely rich in phytoestrogens, are generally not important sources of dietary phytoestrogens in humans. High concentrations are found in red clover, sunflower seeds, and bean sprouts. Coumestans exert significant estrogenic effects when ingested by animals.

Population studies

Studies of populations that consume large amounts of soy phytoestrogens find reductions in rates of a wide variety of cancers, including breast, endometrial, prostate, intestine, and pancreatic disease. In countries such as China and Japan, where the local diet is high in soy foods, women appear to have few menopausal complaints and, coincidentally, the incidence of breast, endometrial, and prostate cancers also is markedly reduced when compared with that in Westernized countries.

Asian diets typically contain 40 to 80 mg of isoflavones per day, whereas American diets average less than 3 mg per day. Western diets elevate plasma levels of sex hormones and decrease sex hormone-binding globulin concentrations, thus increasing the exposure of peripheral tissues to the effects of circulating estrogens. 1 High-soy diets, in contrast, act through several mechanisms to lower effective circulating and tissue levels of steroids. High isoflavone intakes depress LH
levels, and secondarily depress estrogen production. Bean products are rich sources of diphenols, which are thought to lower cancer risk by modifying hormone metabolism and production and limiting cancer cell growth. Bean foods also provide large amounts of fiber, which modifies the level of sex hormones by increasing gastrointestinal motility. Fiber alters bile acid metabolism and partially interrupts the enterohepatic circulation, causing increased estrogen excretion by decreasing the rate of estrogen reuptake in the enterohepatic system. 2

A recently published study by Lu helps to elucidate the magnitude of altered steroid metabolism induced by high isoflavone intake. 3 Women were fed 36 oz of soy milk a day for one menstrual cycle. The calculated intake of isoflavone in this amount of soy milk is approximately 100 mg of daidzein (mostly as daidzin) and 100 mg of genistein (mostly as genistin). Serum estradiol-17b levels dropped by 31% to 81% at various times during the menstrual cycle while the subjects were taking soy milk. Luteal-phase progesterone levels fell by 35% and dehydroepiandrosterone sulfate levels fell by 14% to 30%. Steroid levels remained lower for an additional two or three menstrual cycles. Menstrual cycle length increased from 28.3 to 31.8 ± 5.1 days during the month of soy milk and did not return to pre-study length until five to six cycles later.

This study offers two profound pieces of information. First, when isoflavone intake is increased, endogenous endocrine function is modified very rapidly thereafter. Second, while epidemiologic data evidence that a high isoflavone intake throughout life lowers one's risks of hormone-related cancer, it appears that dietary changes initiated later in life may produce changes in endogenous hormones that are so profound that risk level may fall very shortly thereafter. Like quitting smoking or starting exercise, it may never be too late to start realizing the health benefits of soy isoflavones. Intervention trials with soy foods and isoflavone supplements are under way.

Intervention trials

Very few intervention trials have been done assessing the impact of isoflavones on menopausal symptoms such as hot flashes, dyspareunia and vaginal dryness. Several trials are in process as reported at the Second International Symposium on the Role of Soy in Preventing and Treating Chronic Disease. 4 A nutritional bar containing 40 mg of isoflavones did not ameliorate hot flashes, while a supplement containing isoflavone, 160 mg per day, produced a 50% reduction in the frequency and intensity of mild to moderate vasomotor symptoms.

Albertazzi and colleagues publish a double-blind, parallel, randomized, placebo-control trial with 104 women. 5 Using an isolated soy protein supplement in powder form and a casein placebo, the control group experiences a 30% reduction in hot flashes, while soy-users experienced a 45% reduction. Soy protein is a very large, difficult to digest molecule like the proteins in cow dairy (cassein) and wheat (gluten), so an isoflavone supplement would be a better choice to replace estrogen which can reduce hot flashes by 90%.

Studies are under way to assess whether supplementation with isoflavones can lower rates of primary breast cancer or alter incidence of recurrence in women with antecedent breast cancer. It remains to be seen whether whole soy foods, soy isolates, or isoflavones are effective in modifying patterns of disease. We estimate that between 40 to 160 mg of isoflavones per day may be most beneficial.

Botanicals with accessible published data

All culture's medical traditions include extensive plant pharmacopoeas. Herbal means the leaves and/or stems of plants, while botanical includes any part of a plant, including seeds, flowers, fruits, and roots. More than 50% of medicines in use in the United States are derived from plants.
In their quest to seek relief from menopause-related symptoms and enjoy long-term wellness, American women are combining plant medicines from European, North and South American, and Asian traditions. Most of the botanicals prescribed for menopause and age-related health problems are safe and benign, though they lack the scientific data of approved drugs know to kill over 100,000 Americans each year.

Botanicals for menopausal issues.

Botanical name:	Common name:	Possible negative effects to watch for:
Angelica archangelica L., Angelica atropurpurea L.	Angelica	Photosensitization
Angelica polymorpha Maxim. var Sinensis Oliv, aka A. sinensis (Oliv) Diels	Dong quai, dang gui, tang kuei	Photosensitivity
Arctostaphylos uva-ursi L.	Uva ursi, bearberry	Constipation, possible oxytocic
Caulophyllum thalictroides	Blue cohosh	GI irritation, toxicity
Cimicifuga racemosa	Black cohosh	Nausea and vomiting (high doses)
Ephedra sinica L.	Ma huang	Seizures, cardiac arrhythmia, death
Glycyrrhiza glabra L. (Leguminosae root)	Licorice root	Hyperaldosteronism with Na+ retention and K+ wasting, hypertension (DGL Licorice is recommended because these are effects of glyccyrhizin)
Hypericum perforatum	St. John's wort	Photosensitization, drug-drug interaction with MAO inhibitors
Leonurus cardiaca L.	Motherwort	Photodermatitis
Matricaria recutica L., (Asteraceae) Anthemis nobilis	Chamomile	Allergy
Oenothera biennis	Evening primrose	GI upset, convulsions in combination with phenothaizines
Panax ginseng, Panax quinquifolia	Ginseng, Panax ginseng	Mastalgia, vaginal bleeding, insomnia (American ginseng is more yin and better suited for women)
Senecio aureus	Life root, squaw weed	Toxic: mutagenicity, carinogenicity, hepatotoxicity
Serenoa repens (Batr), S. serrulata (Michx.)	Saw palmetto
Trifolium pratense L. (Fabaceae)	Red clover	(estrogenic)
Turnera diffusa Willd. var aphrodisiaca (L.F. Ward)	Damiana	Convulsions
Urtica dioica L. (Urticaceae)	Nettle	Irritative dermatitis
Valeriana officinalis L.	Valerian	possible dystonic reactions

PDR for Herbal Medicines, 1998

Herbal Medicines: A Guide for Health Care Professionals, 1996

Most commonly, combinations of medicinal plants are used. A limited body of scientific information about botanicals is available in English-language literature accessible in libraries and online. Discussion here is limited to plants for which some amount of literature can be examined.

Black cohosh (Cimicifuga racemosa L. Nutt, family, Ranunculaceae), black snakeroot, or bugbane is sold over the counter as Remifemin in Europe. Duker states that a component of the extract binds competitively to estradiol-17b receptors. 6 He found that black cohosh reduces LH levels in ovariectomized rats, and in a subsequent study, administered Remifemin to postmenopausal women for 8 weeks. Again, LH levels fell, but FSH levels remained unchanged. He concluded that cimicifuga racemosa extract contained "three active compounds... (1) constituents that were not ligands for the estrogen receptor but suppress LH release after chronic treatment; (2) constituents binding to the estrogen receptor and also suppressing LH release; and (3) compounds that are ligands for the estrogen receptor but without an effect of LH release."

The company that manufacturers Remifemin publishes a monograph containing a series of clinical trials showing that black cohosh can offer profound palliation for neurovegetative menopausal symptoms such as anxiety, depression, and other mood disturbances, with significant reductions in the Kuppermans Menopausal Index. Reassuringly, these studies show no estrogen-like effects on target tissues traditionally used as in vivo measures of estrogen effect. Black cohosh is reported to cause no increase in endometrial thickness, no proliferation of vaginal epithelium, and no change in serum LH, FSH, estradiol and prolactin. 7

Clinical trials are under way using a combination of herbals including black cohosh for alleviation of menopause symptoms. Black cohosh should not be confused with blue cohosh (Caulophyllum thalictroides) which has weak nicotine activity and is thought to have toxic potential.

Dong quai, dang gui, tang kuei (Angelica polymorpha Maxim. var Sinesis Oliv, aka A sinensis (Oliv) Diels) is the most commonly prescribed Chinese herbal medicine for female problems, the "sovereign herb for women...." 8 Dong quai regulates and balances the menstrual cycle, and strengthens the uterus. Dong quai is used in traditional Chinese medicine to nourish and tonify the blood, one of the three principal constituents of life along with Qi (energy) and moisture.

Kaiser Permanente conducted a double-blind, control clinical trial with 4.5 g a day of dong quai. Both dong quai and placebo resulted in 25% reduction in hot flashes. Hirata and colleagues state "...dong quai does not produce estrogen-like responses in endometrial thickness or in vaginal maturation and was no more helpful than placebo in relieving menopausal symptoms." 9 Critics of the study have noted that the dose of dong quai was low, since in traditional Chinese herbal medicine, doses over 5 g are often prescribed. Dong quai is rarely used as a single agent.

Dong quai is potentially toxic, as it contains numerous coumadin-like derivatives, and may cause excessive bleeding or drug-drug interactions with other anticoagulants. Dong quai also contains psoralens, and is potentially photosensitizing. A photodermatitis can result, and there is theoretical concern that dong quai could increase risk of sun exposure-related skin cancer. Although dong quai is prescribed for a wide array of female and menstrual disorders, herbal practitioners agree that it is contraindicated during pregnancy and lactation.

Only one study of a combination Chinese preparation can be found in accessible literature. The preparation does not contain dong quai, but it was done by Chinese researchers and published in a journal devoted to traditional Chinese medicine. A placebo was given to control subjects, and liu wei di huang wan, a traditional menopause prescription containing rehmannia, dioscorea, cornus, mountain peony, and alisma, was given masked to the treatment group. The two groups showed no significant improvement in symptoms nor were there any effects on estradiol, gonadotropins, and vaginal cytology. 10

Evening Primrose (evening primrose, evening star, Oenothera biennis L. family onagraceae) produces seeds rich in gamma linolenic acid (GLA) and contains several anticoagulant substances. Commercial preparations made from fixed oil sources are typically 72% cis linolenic acid (LA) and 14% gamma linolenic acid (GLA). Thus 500 mg contains GLA 45 mg and LA 365 mg per capsule plus lesser amounts of oleic, palmitic, and stearic acid.

Because GLA is elaborated by the placenta and high concentrations are found in breast milk, it is said to be the perfect fatty acid for humans. In gynecologic issues, evening primrose is used for mastalgia, mastadynia, premenstrual syndrome, menopausal symptoms, and bladder problems.

Budeiri and colleagues conducted a meta-analysis of clinical trials of evening primrose oil for premenstrual syndrome. 11 Of the seven placebo-control trials, five were randomized and one was double-mask. The double-mask study finds GLA alone ineffective for treating PMS.

Chenoy and colleagues publish the only random , double-mask, placebo-control study with GLA for vasomotor symptoms during menopause. 12 The women taking GLA had "...significant improvement...in the maximum number of night time flushes...," the authors felt that GLA provided no benefits beyond those evidenced with placebo in the total number of vasomotor events per day.

Practitioners recommend 3 to 4 g per day of evening primrose for gynecologic issues and as much as 6 to 8 g per day for dermatologic issues.

St John's wort (Hypericum perforatum). Extracts of this flower have been used for centuries to treat mild to moderate depression. The constituents include hypericin, pseudohypericin, and flavonoids. Several mechanisms of action for the psychotropic effects of St. John's wort have been proposed including MAO inhibition, decreased corticotropin-releasing hormone, and serotonin-receptor blockade. Hypericin does not appear to be an MAO inhibitor.

Fifteen control trials are in a meta-analysis by Linde. 13 Analysis of the 1,757 subjects finds less than 1.2 mg per day of hypericin provides a 61% improvement in mild-to-moderate depression, while higher doses up to 2.7 mg per day produce 75% improvement. Some have suggested that St. John's wort is helpful in treating seasonal affective disorder. Studies in cases of severe depression are limited.

Standard preparations typically contain 0.3% hypericin. The commonly dose recommendation is 2 to 4 g of raw herb or 0.2 to 1.0 mg of hypericin extract per day. Commercial preparations contain 300 mg of 0.3% and the generally recommended dose, one capsule three times a day, provides a cumulative dose just under 3 mg per day. A limited number of side effects have been seen, far less than with standard antidepressant medications, and they include dry mouth, dizziness, and constipation. St. John's wort is potentially photosensitizing.

Grave concerns have been voiced about possible interactions with selective serotonin-reuptake inhibitors (SSRI), and patients who are using or who have recently discontinued the use of MAO inhibitors are cautioned not to use St John's wort for several weeks after stopping the drugs. St. John's wort is contraindicated in pregnancy and lactation.

Valerian root (Valeriana officinalis L. valerianaceae). The common valerian or garden heliotrope has been used for ages as a tranquilizer and sophorific. The effective constituent has never been identified, but it is thought to be a gamma aminobutyric-acid (GABA) derivative. A similar GABA-like compound has been found in chamomile, which also is used as a sleep aid. Before the advent of benzodiazepines and barbiturates, many psychiatric disorders were treated with valerian, which has no demonstrable toxicity and degrades rapidly. Some reports exist of dystonic reactions and visual disturbances. Little is known about valerian root's actions, effects, or potential drug-drug interactions. When taken as an extract, tea, or alcohol tincture, it provides mild, limited, sedating and calming effects without the lingering metabolites that continue to circulate after taking diazepam. After L-tryptophan was taken off the human nutrition market in the Staets, valerian use increased. Despite lack of toxicity, many practitioners recommend against use during pregnancy and lactation.

Typical doses are: dried root, 0.3 to 1.0 g by infusion or decoction three times a day; or using the British Pharmaceutical Codex (BPC), liquid extract, 0.3 to 1.0 mL, tincture 4 to 8 mL; or concentrated infusion, 2 to 4 mL. 13

Botanicals needing more research

Angelica (Angelica archangelica L., Angelica atropurpurea L.). There is no substantiation for therapeutic claims made for this substance. Small amounts are added as a flavoring agent in blending Benedictine and Chartreuse liqueurs. Toxicity has been reported when large amounts of angelica have been ingested to induce abortion. Other potential risks attributed to angelica include photosensitization, mutagenicity, and carcinogenicity.

Chasteberry or Vitex (Agnus castus L. verbenaceae), also known as chaste tree, monk's pepper, agnus castus, indian spice, sage tree hemp, and tree wild pepper. Studies have shown that vitex contains hormone-like substances that competitively bind receptors, producing antiandrogenic effects, hence its use as an antiaphrodisiac, often recommended to reduce libido in males. Antithetically, vitex is then recommended for menopausal women to enhance libido. Studies suggest that vitex can be used to treat inadequate luteal phase, and that it restores LH-releasing hormone activity. It is also recommended for vaginal dryness and depression at menopause. Vitex's antihormonal activity explains its utility in treating mastalgia. Claims are poorly documented.

Damiana (Turnera diffusa Willd. var aphrodisiaca [L.F. Ward]).This has been widely recommended as an aphrodisiac for more than 100 years but there appears to be no documentation for the claims made, and it should be regarded as unsafe.

Licorice, Liquorice (Glycyrrhiza glabra L. Leguminosae root). Prior to the synthesis of mineralocorticoids, licorice was used to treat Addison's disease. Commercial uses include sweetening beer and cigarettes. Commercial "licorice" candies generally are flavored with anise oil. As little as 0.5 to 1.5 g of licorice taken daily for as short a period as 1 week can produce signs of pseudoaldosteronism; fatigue, hypertension, headache, Na+ retention, K+ wasting, shortness of breath, and congestive heart failure have all been reported. Rhadomyolysis has also been seen in one case report. This is due to the component glycyrrhizin, thus deglycyrrhizinated (DGL) licorice is generally preferred.

Nettle (Urtica dioica L. Urticaceae), stinging nettle or common nettle, contains many chemically active substances, including organic acids, amines, and flavonoids. Recommended for a wide array of ailments, it is most often prescribed as a diuretic, a treatment for benign prostatic hypertrophy (BPH), or as an expectorant. It is recommended in menopause to help control menorrhagia. No studies substantiating this claim are known.

Red clover (Trifolium pratense L. Fabaceae). This is a forage plant containing phenols and tannins. Red clover was removed from the USP formulary in 1946, with the authors citing ineffectiveness. In Australia, sheep that grazed on large amounts of subterranean red clover were rendered sterile due to disruption of estrus cycles. No studies in humans can be found about the effect of extracts or concentrates of red clover on female endocrine functions. Promensil, a red clover derivative, exerts its effects through concentrated levels of isoflavones synthesized from the plant, not from the activity of coumestans, which are principally responsible for the effects seen in foraging animals.

Saw palmetto (Serenoa repens (Batr), S. serrulata (Michx.) Nichols). In Europe, a fat-soluble form of saw palmetto is used to treat BPH. The plant extract has minor estrogen-like activity, estimated to be 1/10,000th that of estradiol, while purified beta sitosterol derived from the plant has estrogenicity equal to 1/10th the activity of estradiol. 14 Saw palmetto is also claimed to evidence some antiandrogenic activity, but the mechanism is unknown. Its use in menopause to stimulate flagging libido may be inconsistent with other claims, and is not supported by any source material. In males, saw palmetto provides modest improvements in symptoms of BPH comparable to those seen with finasteride, and it increases peak flow rates in 25%. A recent trial found that urodynamics were slightly improved. 15 A double-blind randomized clinical trial in Germany of 200 men compared a highly refined preparation containing beta sitosterol, 20 mg three times a day, with placebo and found improvements in modified Boyarsky score, International Prostate Symptom score, peak flow, and residual volume. 16

Uva ursi (Arctostaphylos uva ursi L.), bearberry or mountain box is widely recommended as a urinary aseptic and as a bladder sedative. It contains the phenolic glycoside arbutin, which produces hydroquinone, a mild urinary aseptic, but the conversion only takes place when urine is alkalinized. Many women using uva ursi are unaware of this, and render the botanical ineffective by the concomitant use of urinary acidifying agents such as high doses of vitamin C or large quantities of cranberry juice.

Uva ursi should not be regarded as a substitute for antibiotics in treatment of active urinary infection. While American herbal medicine consultants advise taking uva ursi, 500 mg 3 to 4 times a day, European practitioners typically recommend 3 to 6 g a day. Typical preparations include: dried leaves 1.5 to 4 g by infusion three times a day; liquid extract 1.5 to 4.0 mL in 1:1 25% alcohol three times a day; concentrated infusion of 2 to 4 mL; fresh infusion, 15 to 30 mL. Hydroquinone, the active ingredient, is potentially toxic. One gram (equal to 6 to 20 g of plant material) may induce tinnitus, nausea, vomiting, shortness of breath, seizures, and loss of consciousness, while 5 g is lethal.

Uva ursi was one of seven plants studied in the prevention and treatment of renal calculi, including Verbena officinalis, Lithospermum officinale, Taraxacum officinale, Equisetum arvense, Arctostaphylos uva-ursi, Arctium lappa, and Silene saxifraga. All these botanicals reduced stone formation. While herbalists attribute the efficacy of these herbs to supposed urinary aseptic activity and plant saponin steroidal effects, it appears that they work by changing the alkalinity of urine. The authors of the study conclude that these agents provided some benefits, although "...more effective and equally innocuous substances are well known." 17

Other botanicals claimed to have estrogenic activity include:

• ginseng
• fenugreek
• sarsaparilla
• gotu kola
• dong quai
• wild yam

Conclusions:

Patients have come to believe that sincere and empathic treatment of menopause resides in the world of alternative medical practices. Women are suspicious and critical of profiteering and a commercially driven world dominated by managed-care corporations, insurance companies, and pharmaceutical firms.

When given prescriptions for conventional hormone replacement therapy (HRT), many women assert that "we just don't have enough data about hormones." Recent findings on adverse effects of long term estrogen HRT have proven this to be true.

When scientific studies support claims for complementary care, practitioners may comfortably incorporate alternative practices.

For those interested in more detailed information and material about botanicals, The Honest Herbal by Varro Tyler is an excellent and easy-to-read resource. 14 Herbal Medicines: A Guide for Health Care Professionals, edited by Newall, is an encyclopedic reference on botanicals with excellent bibliographic citations from source materials not readily available in the US. 18

The best source for authoritative information about plant medicines is the American Botanical Council, which offers a wide array of books, monographs, and an excellent newsletter, The Herbalgram. They publish an English translation of the seminal German Commission E Monographs on plant medicinals. 19

References:

1. Adlercreutz H, Mousavi Y, Hockerstedt K. Diet and breast cancer. Acta Oncol. 1992;31:175-181.
2. Adlercreutz H. Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab InvestSuppl. 1990;201:3-23.
3. Lu LJ, Anderson KE, Grady JJ, et al. Effects of soya consumption for one month on steroid hormones in premenopausal women: implications for breast cancer risk reduction. Cancer Epidemiol Biomarkers Prev. 1996;5:63-70.
4. Anderson JW, Johnstone BM , Cook-Newell ME: Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med. 1995;333:276-282.
5. Albertazzi P, Pansini F, Bonaccorsi G, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1990;91:6-11.
6. Duker EM, Kopanski L, Jarry H, et al. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med. 1991;57:420-424.
7. Schaper & Brummer GmbH & Co KG. Remifemin(r): The Herbal Preparation for Gynecology: Scientific Brochure. Salzgitter, Germany: Schaper & Brummer, 1997 http://www.schaper-bruemmer.de
8. Beinfield H, Korngold E. Between Heaven and Earth: A Guide to Chinese Medicine. New York, NY: Ballantine Books; 1991.
9. Hirata JD, Swiersz LM, Zell B, et al. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril. 1997;68:981-986.
10. Wu X, Zheng H, Xu R, et al. Comparative effectiveness of Chinese H3 (CH3) and lui wei di huang wan (LWDHW) in female climacteric and their mechanism of action. J Tradit Chin Med. 1987;7:266-268.
11. Budeiri D , Li Wan Po A , Dornan JC. Is evening primrose oil of value in the treatment of premenstrual syndrome? Control Clin Trials.1996;17:60-68.
12. Chenoy R, Hussain S, Tayob Y, et al. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ. 1994;308:501-503.
13. Linde K, Ramirez G, Mulrow CD, et al. St. John's wort for depression-- an overview and meta analysis of randomised clinical trials. BMJ. 1996;313:253-258.
14. Tyler V. The Honest Herbal: a sensible guide to the use of herbs and related remedies. Binghamton, NY: Pharmaceutical Products Press/The Haworth Press; 1993.
15. Dreikorn K, Schonhofer PS. Status of phytotherapeutic drugs in treatment of benign prostatic hyperplasia. Urologe A. 1995;34:119-129.
16. Berges RR, Windeler J, Trampisch HJ. Randomized, placebo-controlled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group. Lancet. 1995;345:1529-1532.
17. Grases F, Melero G, Costa-Bauza A, et al. Urolithiasis and phytotherapy. Int Urol Nephrol. 1994;26:507-511.
18. Newell CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health Care Professionals. London, UK: Pharmaceutical Press; 1996.
19. American Botanical Council, PO Box 201660, Austin, Texas 78720.