Use of Alternative and Complementary Medications for Menopausal Symptoms

1
Use of Alternative and Complementary Medications
for Menopausal Symptoms

• Lorraine A. Fitzpatrick, M.D.
• Professor of Medicine
• Director, Womens Health Fellowship
• Mayo Clinic and Mayo Foundation

2

• Im uncertain about
• taking estrogen. Are there alternative
  medications
• for hot flashes?

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

Naloxone Propranolol Ginseng Yam cream Chinese
Medicinal Herbs
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
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Soy Protein/Isoflavones

• Genistein and daidzein have estrogen-like effects
  on select target tissues
• Estrogenic activity, ERbERa
• 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

Albertazzi P et al. Obstet Gynecol 1998916
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

Clayden JR et al. Br Med J 1974 1409 Hammond MG
et al. J Clin Endocrin Metab 1984 581158 Jones
KP et al. Maturitas 19857135-9.  
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

Source Drugdex Drug Evaluations
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

Lebherz TB, French LT. Obstet Gynecol.
196933795.
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

Stearns V et al. Ann Oncol 20001117-22.
Loprinzi CL et al. J Clin Oncol 1998162377-81.
13
Median Hot Flash Score Reduction in Breast Cancer
Patients
NOT head-to-head trials
Loprinzi C et al
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

Guttoso TJ. Neurology 542161, 2000 Loprinizi CL
et al. Mayo Clin Proceedings, in press, Nov 2002 
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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
2683430-31. DeSmet PAGM. Drug Safety 1995
1381-93.
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Black Cohosh
Cimifuga racemosa Black cohosh
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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!

Liske E. Adv Ther 19981545-53
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Vitex(Chasteberry)
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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 2379. Wuttke W. HN
246, NH 247 Report 1992 87.
21
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 1992167436-439 Cleary C, Fox
JP. Complement Ther Med 19942181-186
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Approach to the Patient Who Refuses (or Cant
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

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Truth is rarely pure,and never simple.

• Oscar Wilde

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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

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Herbal Myths

• Natural Safe
• Used for thousands of years Safe
• Herb as a plant Capsule or Tablet
• All brands of herbs are the same

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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 29.7-42.32

1. The Hartman Group, 1998 2. NHANES III,
1988-1994
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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
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

Prevention Magazine Survey, May 1999
30
Dietary Supplements in 1999 14.9 Billion
Source Nutrition Business Journal, derived form
a variety of sources
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

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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 Annes 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
Womens 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.

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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)
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.

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
Womens Health

• Menopausal symptoms are usually divided into
  three categories (Greene JG Maturitas 1998
  2925-31)
• 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