Managing Menopause with Complementary Therapy

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Managing Menopause with Complementary Therapy

• Rhonda Dorren B.Sc.Pharm.

Heel Canada Inc.
Spring 2004
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Quality of Life Issues

• Women with significant menopausal symptoms will
  continue to request some form of therapy
• Often "natural" supplements
• We will examine
• Estrogen metabolism
• Symptom management
• Discuss some case studies

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The Patient

• Treat the patient
• Protocol-based medicine that ignores individual
  characteristics may be "safe"
• May never give the best results for the
  individual
• Options to attend to this

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Menopausal Women

• Manage a barrage of symptoms
• Physiological
• Psychological
• Increased risk of age-related disease
• Often seek natural support
• Menopause is not a disease it is a natural
  transition and may not require drugs

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Signs Symptoms of Menopause

• Elevated FSH and LH levels
• Hot flashes/flushes or night sweats
• Decreased vaginal lubrication/thinned vaginal
  mucosa
• Mood swings
• Dry hair/hair loss

• Insomnia
• Anxiety/Depression
• Forgetfulness and impaired concentration
• Urinary incontinence
• Loss of libido
• Natural menopause usually age 50-51

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Additional Considerations in Menopause

• Cancers
• Endometrium
• Breast

• Modify risk factors
• Exercise
• Stress reduction
• Diet

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Estrogen and Menopause

• Estradiol (E2)
• Most potent estrogen
• Falls after menopause
• Estrone (E1)
• Most predominant in womens bodies after
  menopause
• With the decline in ovarian function, fat cells
  synthesize most of the Estrone

• Estriol (E3)
• Weak estrogen
• Comes from Estrone and Estradiol
• Dr. D.H. Lemons Estrogen quotient is a ratio of

Estriol Estrone Estradiol
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Estrogen Quotient

• A higher ratio of
• Estriol alone compared to EstroneEstradiol
• Yields a decrease in Breast Cancer Risk
• In healthy women this ratio is
• Premenopausal 1.3
• Postmenopausal 1.2

• In breast cancer women the ratio is
• - Premenopausal 0.5
• - Postmenopausal 0.8
• Conclusion women with breast cancer have low
  levels of Estriol relative to other forms of
  estrogen

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Restoring Hormonal Balance

• Tri-Est
• Estradiol 10
• Estrone 10
• Estriol 80
• Available at compounding pharmacies in
  capsules and topical creams or gels

• Progesterone
• Testosterone
• Available in capsule form or at compounding
  pharmacies in creams or gels

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Protocol Strategies

• Marriage of
• Responding to patient symptoms
• Respecting patients beliefs
• Applying knowledge of the science of hormone
  balance and detoxification
• Selecting most appropriate course of action

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Hormones in Women
Hypothalamus
Pituitary
Adrenals
Androstenedione, DHEA, DHEAS, Cortisol
ACTH
Gonadotropin Releasing Hormone (GnRH)
Ovary
FSHLH
Androstenedione Testosterone Estrogens
Androstenedione DHEAS
Extraglandular sites
Testosterone
Estradiol
Testosterone
Skin and Fat
Estrone
Androstenedione
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Estrogen Metabolism and Detoxification

• Primarily in the liver through
• Phase I (hydroxylation) pathways
• Phase II (methylation, glucuronidation
  sulfation) pathways
• Ultimate excretion in the urine and feces

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Estrogen - Hydroxylation

• Cytochrome P450 ENZYMES mediate hydroxylation of
  estradiol and estrone
• This is the major Phase I metabolic pathway for
  endogenous estrogens

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Estrogen - Hydroxylation

• Takes place at two primary sites on estrogen
  molecule
• 1. 2 carbon (C-2) position?
• 2-hydroxyestrone (2-OH)
• 2. 16?-carbon (C-16?) position ?
• 16?-hydroxyestrone (16?-OH)
• Minor contribution from
• 4 carbon (C-4) position ?
• 4-hydroxyestrone (4-OH)

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Estrogen - Hydroxylation
Catechol Estrogens

• 2-OH Metabolite
• weak estrogenic activity
• good estrogen

• 16 ?-OH 4-OH Metabolite
• promote estrogenic activity and promote tissue
  proliferation
• undesirable estrogen

Women metabolizing most endogenous estrogen
via 16?-hydroxylation are at ? risk of breast
cancer compared with women who metabolize more
estrogen through the C-2 pathway
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Catechol Estrogen Metabolism
2-0H (catechol estrogen)
DNA Damage
oxidize
Quinones (highly reactive)
oxidize
4-OH (catechol estrogen)
Generate Reactive Oxygen Species (promote
carcinogenesis) superoxide, hydrogen peroxide,
hydroxyl radicals
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Estrogen - Glucuronidation

• Major Phase II liver detoxification pathway
• Estrogen and other toxins
• Glucuronic acid conjugates with estrogen
• Facilitates elimination from the body
• Pathogenic
  intestinal
  
  bacteria produce
  ?-glucuronidase

Complication
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Impact of excess ?-glucuronidase
Glucuronic acid
Glucuronic acid
bond
?-glucuronidase
Excreted estrogen
uncouples bond
Large Intestine
Excreted estrogen
Excess ?-glucuronidase activity is associated
with increased cancer risks including breast
cancer
re-enters enterohepatic
circulation
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Estrogen Methylation

• Goal minimize pathway to harmful quinones
• Must promote Phase II methylation pathways
• Detoxifies and excretes catechol estrogens
• Requires catechol-O-Methyltransferase (COMT)
  enzyme
• Co-factors are S-Adenosylmethionine (SAM) and
  magnesium

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Reducing ?-glucuronidase Activity

• Activity is increased with diet high in fat and
  low in fiber
• Modify diet to include low fat and high plant
  fiber
• Supplement with
• Lactobacillus acidophilus
• Bifidobacterium infantis

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Breast CancerRatio of 2-OH to 16?-OH

• Premenopausal women who developed breast cancer
  had
• Lower 2-OH16?-OH ratio
• Higher percentage of 16?-OH than 2-OH
• Higher 2-OH reduces risk of developing breast
  cancer by 40?
• Postmenopausal women with highest
  2-OH16?-OH ratios had 30? lower risk of breast
  cancer

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Modifying Metabolic Status

• Pesticides
• Carcinogens
• Drugs
• Obesity
• Genetic predisposition

• Dietary interventions
• Increase cruciferous vegetables
• Broccoli
• Cabbage
• Phytoestrogen-rich foods
• Soy/flax seeds

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Nutritional Modulation Carbohydrates

• Simple carbohydrates
• Raise blood glucose levels
• Stimulate insulin release
• Secondary adverse influence on sex hormone
  balance
• Complex carbohydrates attenuate
• Glycemic response
• Insulinemic response

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Nutritional Modulation Fats

• Balance among types and amounts of fats important
  in estrogen equilibrium
• Breast cancer cells exposed to eicosapentaenoic
  acid (Omega-3 fatty acid) found in cold water
  fish showed estradiol metabolism
• Increased C-2 hydroxylation
• Decreased C-16? hydroxylation

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Nutritional Modulation Dietary Fiber and Lignin
Different than Lignans

• Lignin is an insoluble dietary fiber
• Flax seeds
• Bran layer of grains, beans and seeds
• Binds unconjugated estrogen in the digestive
  tract
• Affects composition of intestinal bacteria
• Reduces ?-glucuronidase activity
• Lowers deconjucation of estrogen and reduces
  reabsorption
• Increases serum SHBG
• Reduces levels of free estradiol

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Nutritional Modulation Protein

• Inadequate protein may lead to decreases in
  overall cytochrome P450 activity
• Including cytochrome P450-1A2 which detoxifies
  estradiol
• Rice is a source of protein frequently used to
  nutritionally support hepatic detoxification

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Nutritional Modulation Vitamin E

• Low serum levels associated with elevated
  estrogen levels
• In vivo and vitro growth of breast cancer cells
  inhibited by postulated mechanism
• Inhibits expression of vascular endothelial
  growth factor
• Prompts angiogenesis
• Deficiency may negatively affect cytochrome P450
  function
• Impacts estrogen detoxification

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Nutritional Modulation Magnesium

• Essential cofactor for the Catechol-O-
  Methyltransferase (COMT) enzyme
• Optimizes the methylation and excretion of
  catechol estrogens
• Increases activity of glucuronyl transferase
• Enzyme in hepatic glucuronidation
• Promotes estrogen detoxification
• Ovarian hormones can negatively influence
  magnesium levels
• Altered calcium magnesium ratios

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Nutritional Modulation B Vitamins

• B6, B12, and folate are important cofactors for
  enzymes in estrogen conjugation and methylation
• Folate essential cofactor for 2-OH and 4-OH
• Reduces conversion to quinones
• Intracellular active vitamin B6 may decrease gene
  transcription responses when estrogen binds to
  the estrogen receptors (ER)
• Crucial for DNA synthesis, repair and DNA
  methylation

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Nutritional Modulation Phytoestrogens

• Plant compounds that bind to ERs
• Estrogenic and anti-estrogenic effects
• Expression dependent on ER subtypes in target
  cells
• Level of endogenous estrogen present
• Investigated for a range of conditions associated
  with estrogen imbalance
• Two main classes
• Isoflavones
• Lignans

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Nutritional Modulation Phytoestrogens

• Influence estrogen synthesis and metabolism
• Similar structure to estradiol and bind to ERs
• Thought to increase plasma sex hormone-binding
  globulin (SHBG) levels
• Decrease aromatase activity
• Shift estrogen metabolism away from the C-16?
  pathway to the C-2 pathway

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Nutritional Modulation Phytoestrogens

• Studies
• Low fat vegetarian diets showed a 19 increase in
  mean serum SHBG levels
• Two studies showed increased isoflavones
  consumption
• Decreased urinary excretion of 16?-OH and 4-OH
• Increased the 2-OH16?-OH ratio

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Nutritional Modulation Lignans

• Found in fiber rich foods
• Flax seed and other oil seeds
• Whole grains
• Legumes
• Vegetables
• Intestinal fermentation converted to
• Enterolactone
• Enterodiol
• Stimulate production of SHBG in the liver
• Reduces levels of free estrogen in circulation

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Nutritional Modulation of Estrogen Metabolism -
Lignans

• Enterolactone inhibits aromatase activity
• Decreases conversion of testosterone and
  androstenedione into estrogens in fat and breast
  cells
• Lignans also inhibit estrogen sensitive breast
  cell proliferation
• Women who consumed 10 g of flax seed daily
  experienced
• Longer menstrual cycle length
• Increased progesterone-to-estrogen ratios
• Fewer anovulatory cycles

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Nutritional Modulation Isoflavones

• Most common source is soy
• Also legumes, alfalfa, clover, licorice root,
  and kudzu root
• Biologically active isoflavones
• Genistein, daidzein, equol, puerarin
• Plant precursors include formononetin, biochains,
  genistin and daidzin

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Nutritional Modulation Isoflavones

• Women given 45 mg of isoflavones daily for 1
  month experienced
• Longer menstrual cycles
• Lower Luteinizing Hormone (LH)
• Lower Follicle Stimulating Hormone (FSH) levels
• Women taking 69 mg of isoflavones with low level
  SHBG
• Increased SHBG concentrations

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Positive Trials of Soy in Treatment of Hot Flushes
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Study by Albert et al. 2002 on Isoflavones

• Multicentric, open, prospective, observational
  non randomized clinical trial Spain
• 190 postmenopausal women 35 mg/d
• 4 months of treatment 80 experienced
  statistically significant decreased number of hot
  flushes daily
• No side effects and excellent tolerance

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IsoflavonesTherapeutic Use

• Hot flushes and night sweats
• Cardiovascular diseases
• Osteoporosis
• Take part from thyroid medication by at least 3
  hours
• Individuals with impaired thyroid function or
  with iodine deficiency
• Use soy supplements with caution

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Equifem?-Balance

• Each capsule contains 20 mg of isoflavones
• Soy extracts (concentrated in isoflavones)
• Take 2 capsules daily
• Morning and evening
• Do not exceed 5 capsules daily
• 100 mg isoflavones daily
• Take throughout the day for best results

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Vaginal Atrophy

• Vaginal dryness
• Consequence of vaginal atrophy
• Common complaint for menopausal women
• Incidence of urogenital atrophy
• 15 of premenopausal women
• 10-40 of postmenopausal women
• 10-25 of women receiving systemic HRT hormone
  therapy
• Common symptoms
• Dryness, burning, pruritus, irritation, bleeding,
  dyspareunia (painful intercourse)

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Vaginal Atrophy

• Epithelial cells of vagina contain
• Highest number of estrogen binding sites of any
  genital structure
• Higher in the postmenopausal vagina
• Progressive depletion of estrogen during
  postmenopausal years decreases
• Percentage of superficial cells
• Normal vaginal secretions
• Vaginal surface becomes fragile, bleeding occurs
  with minimal trauma

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Vaginal Atrophy

• Estrogen responsible for deposition of glycogen
  in the vaginal epithelium
• Declining estrogen
• Absence of glycogen-containing superficial cells
• Results in decreased production of lactic and
  acetic acids
• Results in abnormally alkaline vaginal pH
• Creates a milieu that favors infection

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Vaginal Atrophy

• Lubrication and hydration is decreased
• Even with sexual stimulation
• Loss of lubrication leads to
• Vaginitis, vaginismus (painful spasm of the
  vagina preventing intercourse), pruritus and
  dyspareunia
• Current studies assessing the effect of
  phytoestrogens on vaginal cytology
• Demonstrated significant reduction in vaginal
  dryness

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Equifem Vaginal Gel

• Provides a gentle trophic (nutritional) action on
  the vaginal epithelium
• Long-lasting effect in restoring
• Elasticity and integrity of the vaginal membrane
• Vaginal pH
• Alleviates dryness (hydrating vaginal epithelium)
• Stimulates cellular renewal and helps
  reconstitute the vaginal epithelium

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Equifem Vaginal Gel

• Pre-filled applicators (7 ml each)
• Composition per tube
• Extract of soy isoflavones (non genetically
  modified)
• Provides 3.5 mg of isoflavones per single dose
  (applicator)
• Non-medicinal ingredients water, glycerin,
  mineral oil, carbomer, phenoxyethanol, sodium
  hydroxide, methylparaben, butylparaben,
  ethylparaben, propylparaben

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Equifem Vaginal Gel

• Best results
• 1 applicator twice a week (3 days apart) for 4
  weeks, decrease to 1 applicator once weekly for
  another 4 weeks
• Once dryness is alleviated, use when necessary
• Rapid relief may be experienced within a few
  weeks of use
• May be repeated for continuing benefits
• May notice a slight discharge
• Possibly use a sanitary pad

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Equifem?-Mood

• Glutamic Acid (HCl) 50 mg
• Pyridoxine (HCl) Vitamin B6 50 mg
• Black cohosh (Cimicifuga racemosa) 30 mg
• White Korean ginseng (Panax ginseng radix) root
  20 mg
• Folic Acid 0.33 mg

• No colouring agents
• GMO Free
• Vegetarian
• Take 2 to 3 capsules daily in divided doses, as
  needed

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• Responding to a stressful stimulus (or
  pathological condition)
• Corticotropin-releasing factor (CRF) is released
  from hypothalamus
• Causing the pituitary gland to secrete the
  hormone corticotropin (ACTH)
• Triggers the release of glucocorticoids
  (cortisol) from the adrenal gland
• This signaling chain is hypothalamus-pituitary-a
  drenal axis (HPA) or the "stress axis
• Plays an important role in the adaptation of the
  organism responding to stressful stimuli
• HPA axis may be disrupted in depression or anxiety

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Equifem?-Mood Glutamic Acid

• Helps maintain acid-alkaline balance
• Modulates hypothalamus-pituitary-adrenal axis
• Stress axis
• Precursor to gamma-aminobutyric acid (GABA)
• Brain neurotransmitter for mental activity
• Regulates moodiness, irritability, anxiety,
  insomnia, depression

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Equifem?-MoodVitamin B6

• Involved in numerous metabolic reactions
• Transmission of amino acids
• Conversion of tryptophan to niacin
• Synthesis of GABA, serotonin, norepinephrine, and
  dopamine
• Therefore regulates
• Humor, sleep patterns, depression, anxiety,
  general behaviour

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Equifem?-MoodBlack Cohosh

• Suppresses secretion of luteinizing hormone (LH)
• Hot flushes
• Heart palpitations
• Headaches
• Relieves psychological menopausal symptoms

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Equifem?-MoodWhite Korean Ginseng

• Triterpenoid saponins
• Ginsenosides
• Affect stress axis
• Decrease serum cortisol concentration
• Stimulate adrenal function
• Increase dehydroepiandrosterone sulfate (DHEA-S)
• Reduced in menopause-may contribute to
  psychological symptoms

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Equifem?-MoodFolic Acid

• Contributes to the production of
  neurotransmitters
• Serotonin
• Dopamine
• Synthetic folic acid -100 bioavailable
• 40 bioavailable in food
• Deficiency associated with
• Irritability, forgetfulness, hostility, depression

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Consumers Needs

• Consumers are looking for products that
• Are GMO free
• Contain the least additives
• Are completely vegetarian
• Are easy to take

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Alternative Protocol
Dissolved in the mouth (under the tongue)
Also available in vials
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Other Helpful Remedies
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Supplement Doses
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Case Study 1

• 54 year old women suffering from symptoms of
  menopause
• Hot flushes
• Insomnia
• Weight gain
• Lack of concentration

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Case Study 2

• 42 year old women suffering from symptoms of
  perimenopause
• Lack of ability to concentrate
• Very fatigued throughout the day
• Cannot sleep throughout the night
• Menstrual periods occurring more frequently

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Case Study 3

• 60 year old women recently off of HRT suffering
  from menopausal symptoms
• Hot flushes
• Weight gain
• Headaches
• Anxiety

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Case Study 4

• 51 year old women just entering menopause with
  menopausal symptoms (will not take soy
  isoflavones)
• Hot flushes
• Impaired concentration
• Cannot sleep throughout the night
• Feels tired all of the time

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Case Study 5

• 48 year old women who only has menstrual period
  every 3 to 4 cycles
• Suffering from insomnia (cant fall asleep or
  stay asleep)
• Lack of energy
• Difficulty to concentrate
• Irritable

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THANK YOU

• For more information call
• Heel Canada Inc.
• 1-888-879-4335
• Fax [phone]
• email info_at_heel.ca

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