Use of Alternative and Complementary Medications for Menopausal ...

1. 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

3. Epidemiology of Hot Flashes 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 indefinitely More common in Afro-Americans Some cultures have no symptoms

4. 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

5. Vitamin E and Vitamin C Vitamin E Used since the 1940s Reduced hot flashes only 10% above placebo Flavinoids combined with vitamin C Offensive body odor, stains clothing

6. Soybeans

7. Soy Protein/Isoflavones Genistein and daidzein have estrogen-like effects on select target tissues Estrogenic activity, ERb>ERa Not noted dramatic effects compared to placebo (~15% over placebo in only one study) Unknown long-term effects on estrogen-sensitive tissues; soy components stimulate breast tumors in nude mice

8. 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

9. 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

10. Antidopaminergic Agents Veralipride is a substituted benzamide derivative with anti-dopaminergic (D2) and anti-gonadotropic activity Attenuated hot flashes in double-blind study; as effective as 1.25 mg CEE Not approved for use by FDA in US Associated with mammary gland discharge, somnolence, median weight increase of 5 kilograms, chronic hyperprolactinemia

11. 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

12. 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

14. Therapies for Hot Flashes Things that might work; appropriate trials not available SSRIs SERMs Mirtazapine Gabapentin Black cohosh Vitex

15. Gabapentin Related to GABA neurotrainsmittor; action not established Only preliminary trials, not placebo-controlled Attenuated hot flashes in hypogondal men with prostate cancer and in women with breast cancer Associated with anorgasmia in men and women

16. 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

17. Black Cohosh

18. 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 estrogen-like effects Preparations vary widely!

19. Vitex(Chasteberry)

20. 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

21. Other Modalities Meditation, applied relaxation Acupuncture Magnetic therapy (placebo was better) Hypnosis Biofeedback Deep breathing exercises, training paced respiration

22. 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

23. Truth is rarely pure,and never simple. Oscar Wilde

24. Clinical Trials for Hot Flashes Careful patient selection (most trials to date in breast cancer patients on SERMs) Placebo controls Double-blind, double-dummy Lead-in period Cross-over trial designs Validated measures and outcomes No confounding medications

25. Back up slides

26. Herbal Myths Natural = Safe Used for thousands of years = Safe Herb as a plant = Capsule or Tablet All brands of herbs are the same

27. 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 41.8-55%; adult men 29.7-42.3%2

28. 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

29. 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 non-prescription 30% are using with an non-prescription

30. Dietary Supplements in 1999: $14.9 Billion

31. 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

32. 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

33. History of Phytoestrogens Queen Anne�s lace (wild carrot) Contraception Pomegranate Love, fertility Pollens of date palm Fertility induction Moghat root 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

34. 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

35. 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

36. 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.

37. 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

38. 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. The sheer volume of herbal products consumed in pursuit of health obligates the health care provider to expand his or her knowkedge of the these substances to suport the positive efforts of the patient to achieve wellness while directing them to therapies with proof of efficacyThe sheer volume of herbal products consumed in pursuit of health obligates the health care provider to expand his or her knowkedge of the these substances to suport the positive efforts of the patient to achieve wellness while directing them to therapies with proof of efficacy

39. 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.

40. 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

41. 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

42. 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?

43. 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

44. 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

45. 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