Use of Alternative and Complementary Medications for Menopausal Women

Use of Alternative and Complementary Medications for Menopausal Symptoms Lorraine A. Fitzpatrick, M.D. Professor of Medicine Director, Women’s Health Fellowship Mayo Clinic and Mayo Foundation “I’m uncertain about taking estrogen. Are there alternative medications for hot flashes?” Therapies for Hot Flashes Things that do not work very well, if at all Vitamin E Evening primrose oil Soy isoflavones Dong quai Red clover Naloxone Propranolol Ginseng Yam cream Chinese Medicinal Herbs Therapies for Hot Flashes Things that work, but not as good as estrogen Progestins Androgens Tibolone (estrogenic, androgenic and progestogenic properties) Alpha-adrenergic agonists Anti-dopaminergic agents Bellergal Selective Serotonin Reuptake Inhibitors Antihypertensives and Hot Flashes • Alpha-adrengergic agonists (clonidine, lofexidine, methyldopa) reduce hot flashes 20-65% • Alter neurotransmitters in the hypothalmus to regulate thermoregulatory center • High dropout rates in clinical trials • Dizziness, dry mouth Clayden JR et al. Br Med J 1974; 1:409 Hammond MG et al. J Clin Endocrin Metab 1984; 58:1158 Jones KP et al. Maturitas 1985;7:135-9. Bellergal-S • “Spacetabs” • Ergotamine tartrate, belladonna alkaloids and phenobarbital • Reduces hot flashes by 42% over placebo • “Autonomic system stabilizer” that inhibits sympathetic-parasympathetic pathway • Potential for addiction Lebherz TB, French LT. Obstet Gynecol. 1969;33:795. SSRIs and Hot Flashes • Selective serotonin reuptake inhibitors • Efficacy with venlafaxine, paroxetine, fluoxetine, sertraline (~ 75% compared to 30% placebo response) • Trials in breast cancer patients on SERMs suggests effects may be under rated • 2-23% experience sexual dysfunction Stearns V et al. Ann Oncol 2000;11:17-22. Loprinzi CL et al. J Clin Oncol 1998;16:2377-81. Median Hot Flash Score Reduction in Breast Cancer Patients 100 80 Placebo (n=347) Soy (n=66) Clonidine (n=75) Fluoxetine (n=20) Vitamin E (n=57) Median 60 40 20 NOT head-to-head trials Venlafaxine (n=45) Megestrol (n=74) 0 Baseline Loprinzi C et al 1 2 3 4 Week Therapies for Hot Flashes Things that might work; appropriate trials not available SSRIs SERMs Mirtazapine Gabapentin Black cohosh Vitex Botanical Medicine • Mislabeling and under-labeling • Substitution of herbs • Presence of toxic metals in a number of traditional Chinese medicines • Presence of conventional Western pharmaceuticals in traditional Chinese medicines: corticosteroids, NSAIDS, estrogens, progesterone, diazepam • Inconsistent preparations Schaumburg HH, Berger A. JAMA 1992; 268:3430-31. DeSmet PAGM. Drug Safety 1995; 13:81-93. Cimifuga racemosa Black cohosh Black Cohosh Cimicifuga Racemosa (Black Cohosh) • Inconsistent results from less than rigorous trials (7/8 without placebo) • Approved and reimbursable in Germany • Daily dose of 20 to 40 mg for 6 months • 25-30% improvement in attenuation of hot flashes over placebo • Properties probably not due to estrogenlike effects • Preparations vary widely! Liske E. Adv Ther 1998;15:45-53 Vitex (Chasteberry) Vitex (Chasteberry) • German E commission approves for menstrual irregularities and mastodynia • Anti-androgenic effects? • May raise progesterone levels • Proposed mechanisms of action: Increases secretion of luteinizing hormone Improves “progesterone deficiency” Inhibits prolactin Loch E. Di; TW Gynakol 1989; 2:379. Wuttke W. HN 246, NH 247 Report 1992; 8:7. Other Modalities • Meditation, applied relaxation • Acupuncture • Magnetic therapy (placebo was better) • Hypnosis • Biofeedback • Deep breathing exercises, training paced respiration Towlerton G et al. Palliative Medicine. 13(5):445, 1999 Carpenter JS et al. Cancer Nursing. 25(2):104-9, 2002 Wijma K. Journal of Behavior Therapy & Experimental Psychiatry. 28(4):251-61, 1997 Freedman RR, Woodward S. Am J Obstet Gynecol 1992;167:436-439 Cleary C, Fox JP. Complement Ther Med 1994;2:181-186 Approach to the Patient Who Refuses (or Can’t Take Estrogen) • • • • • • • Diary to assess triggers Exercise Smoking cessation Avoid spicy food, caffeine and alcohol Layered clothing Low ambient temperature First line: SSRIs – Second line: Clonidine – For the patient who wants to do it “naturally”: black cohosh Truth is rarely pure, and never simple. Oscar Wilde Back up slides Herbal Myths Natural = Safe Used for thousands of years = Safe Herb as a plant = Capsule or Tablet All brands of herbs are the same How Many People Use Dietary Supplements?  Estimated 40-55% of Americans use supplements- on a regular basis: >100 million people  Estimated 69% use vitamin & mineral supplements; 24% use herbal supplements1  Users predominantly adult women 41.855%; adult men 29.7-42.3%2 1. The Hartman Group, 1998 2. NHANES III, 1988-1994 Why Do People Take Dietary Supplements?      Feel better Prevent illness Improve recovery when sick Build strength and muscle Doctor suggested taking supplements   Live longer Lose weight Source: Yankelovich Partners Inc. for NNFA, 2000 How are Consumers Using Herbal Products? 36% are using instead of prescription medication 31% are using with prescription medication 48% are using instead of an nonprescription 30% are using with an non-prescription Prevention Magazine Survey, May 1999 Dietary Supplements in 1999: $14.9 Billion Minerals $1.2 billion Vitamins $5.8 billion Herbs/ Botanicals $4.4 billion Other Supplements $2.0 billion Sports Nutrition $1.5 billion Source: Nutrition Business Journal, derived form a variety of sources Ideal Treatment for Postmenopausal Women • Decrease or prevent vasomotor symptoms • Increase BMD and decrease fracture risk • Neutral or positive effects on cardiovascular system • Decrease risk for breast cancer • Positive cognition and/or libido effects • Ease of administration Definition • Phytoestrogen is any plant compound structurally and/or functionally similar to ovarian and placental estrogens and their active metabolites • Compounds may have agonistic, partial agonistic, and antagonistic interactions with estrogen receptors and other targets of estrogenic steriods involved in estrogen transport, synthesis and metabolism History of Phytoestrogens Queen Anne’s lace (wild carrot) Pomegranate Pollens of date palm Moghat root Contraception Love, fertility Fertility induction Postpartum beverage Over 300 plants Associated with reduction in chronic diseases Effects vary with concentration, concentration of endogenous estrogen, gender and menopausal status, variability in colonic microflora Phytoestrogens • At least 20 compounds from over 300 plants Herbs (parsley, garlic) Grains (soy beans, wheat, rice) Fruits (dates, cherries, apples) Drinks (coffee and wine) • Weaker than natural estrogens • Easily broken down, not stored in tissue Clinical Recommendations • Postmenopausal women perceive prescription estrogens as “unnatural” • Many prescription estrogens are derived from plant or other natural sources • Potential for problems in premenopausal women, but no evidence • Reported cases of vaginal bleeding in postmenopausal women: avoid overuse • Recommend moderation in postmenopausal women Women’s Health • Most American women will spend the last 1/3 of their lives post-menopause. • While the medical community advocates the use of hormone therapy, many women are seeking alternative approaches to their menopausal symptoms. Soy and Hot Flashes • Double-blind 6 month study on menopausal symptoms • 69 peri-menopausal women • Treatments Isoflavone rich soy protein Isoflavone poor soy protein • No effect on vasomotor or menopausal symptoms A S Germain et al Menopause :8, 17 (2001) Botanical Medicine • The sale of dietary supplements and extracted herbs is a multi-billion dollar business. • Consumers are confused about what supplements to use and do not know what to ask. • Health care providers are inadequately prepared to answer questions. Botanical Medicine • Lack of consensus among experts regarding dosage, safety, herb-drug interactions, and length of treatment. • Scientific studies vary in quality, lack of objective outcome and measurements, short duration and incomplete descriptions. Botanical Medicine • What about herb-drug interactions and side effects? Opposing mechanisms of actions Anti-coagulants Drugs with a “narrow” therapeutic window There is absolutely no way of knowing with 100% certainty which herbs will react with specific drugs First trimester of pregnancy Women’s Health • Menopausal symptoms are usually divided into three categories (Greene JG: Maturitas 1998: 29:25-31): • Vasomotor symptoms: hot flashes, night sweats • Somatic symptoms: headaches, joint pain • Psychological symptoms: depression, irritability Potential Problems? • Can isoflavones induce goiter by inhibition of thyroid peroxidase? • Do isoflavones promote or inhibit breast cancer? Other cancer types? • Inverse relationship between soy intake and testosterone concentrations? Inhibition of 17B hydroxyreductase? Male infertility? • Decrease follicular cell atresia resulting in multiple gestations? Lengthened luteal phase? • In men, high levels of tofu associated with low cognition scores? • Soy for infants causing long-term developmental problems? Pathophysiology of Hot Flashes • Result from estrogen withdrawal Natural menopause Surgical menopause GnRH agonists or antagonists • 75% Caucasian women experience hot flashes, beginning 2 years prior to cessation of menses 85% have flashes for more than 1 year 25-50% for 5 years May continue indefinately • More common in Afro-Americans Some cultures have no symptoms Pathophysiology of Hot Flashes • Vasomotor instability with individual differences in frequency, duration and intensity (ave time 4 minutes) • Influenced by environmental and physiologic influences • Prodrome • ?Paroxysmal firing of neurons in temperature regulatory center • Neuronal firing in reticular activing center causes awakening • Interactions among catecholamines, prostagladins, endorphins, neuropeptides Progestins and Hot Flashes • Depo-medroxyprogesterone acetate attenuates hot flashes Up to 85% reduction at 150 mg Oral MPA (10 mg qd) reduces by 87% Mastalgia, mood changes, bloating, weight gain, irregular vaginal bleeding Concerns raised over the WHI results