1 menopause barbara sproule, pgy-5 university of ottawa the ottawa hospital

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Menopause Menopause

Barbara Sproule, PGY-5Barbara Sproule, PGY-5University of OttawaUniversity of OttawaThe Ottawa HospitalThe Ottawa Hospital

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ObjectivesObjectives Review the definitions and physiology of perimenopause and menopause in Review the definitions and physiology of perimenopause and menopause in

relation to menstrual cycle changes and fertility relation to menstrual cycle changes and fertility Correlate the described physiologic changes with the clinical presentation of Correlate the described physiologic changes with the clinical presentation of

menopause, including common signs and symptoms of menopausemenopause, including common signs and symptoms of menopause Describe the effects of hormonal changes in the post menopausal woman on Describe the effects of hormonal changes in the post menopausal woman on

lipid metabolism, the cardiovascular system and bone metabolismlipid metabolism, the cardiovascular system and bone metabolism

ObjectivesObjectives

Describe the bio psychosocial impact Describe the bio psychosocial impact of menopauseof menopause

Describe appropriate investigations in Describe appropriate investigations in the post menopausal womanthe post menopausal woman

Describe pharmacologic and non Describe pharmacologic and non pharmacologic approaches to pharmacologic approaches to management of menopausal symptoms management of menopausal symptoms as well as side effects of treatment on as well as side effects of treatment on other organ systemsother organ systems

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DefinitionsDefinitions

Menopause :Menopause :

Defined as 12 months of amenorrhea after the final/ Defined as 12 months of amenorrhea after the final/ last natural menstrual period. It results from the loss last natural menstrual period. It results from the loss of physiological ovarian function.of physiological ovarian function.

Menopause is equal to one day in a woman’s life.Menopause is equal to one day in a woman’s life.

The woman is referred to as being The woman is referred to as being post menopausalpost menopausal once the 12 months of amenorrhea have elapsed.once the 12 months of amenorrhea have elapsed.

The average age is 51.4 years, however anytime The average age is 51.4 years, however anytime between the ages of 45 and 55 is considered normal.between the ages of 45 and 55 is considered normal.

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Menopause (Last Natural Period)

Symptoms

Postmenopause

45 y 50-55 y

PremenopausePerimenopause

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DefinitionsDefinitions Early menopause occurs between the ages of Early menopause occurs between the ages of

40-45.40-45.

Loss of ovarian function occuring before the Loss of ovarian function occuring before the age of 40 is referred to as premature ovarian age of 40 is referred to as premature ovarian failure/insufficiency. This results in early loss failure/insufficiency. This results in early loss of the protective effects of estrogen and may of the protective effects of estrogen and may increase risk for osteoporosis and heart increase risk for osteoporosis and heart disease later in life. disease later in life.

Late menopause occurs after the age of 55 and Late menopause occurs after the age of 55 and results in a longer exposure to estrogen. results in a longer exposure to estrogen.

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DefinitionsDefinitions Perimenopause :Perimenopause :

A transition period leading to menopause A transition period leading to menopause beginning with altered ovarian hormone beginning with altered ovarian hormone production.production.

Lasts 2-8 years with an average duration of 5 Lasts 2-8 years with an average duration of 5 years before the last menstrual period, and years before the last menstrual period, and continues until 1 year after the last natural continues until 1 year after the last natural menstrual period.menstrual period.

May start as early as the mid 30s.May start as early as the mid 30s.

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DefinitionsDefinitions

PerimenopausePerimenopause Associated with fluctuating hormone levels Associated with fluctuating hormone levels

varying within the same cycle (low-normal-varying within the same cycle (low-normal-high)high)

Varied symptoms of menopause as well as Varied symptoms of menopause as well as symptoms of estrogen excess, such as symptoms of estrogen excess, such as breast tenderness, all within the same cycle.breast tenderness, all within the same cycle.

Characterized by irregularity of menstrual Characterized by irregularity of menstrual cycles and anovulation.cycles and anovulation.

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Menstrual Periods in the Menstrual Periods in the PerimenopausePerimenopause

35 40 45 50Regular cycles

Shortened cycles

Irregularcycles

Periodscease

Estrogen deficiencysymptoms

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Age at MenopauseAge at Menopause

00

5050

100100

4040 4545 51.51.44

5555 6060

Pre- mature

LateEarly Average

Perc

en

tag

e o

f Perc

en

tag

e o

f w

om

en

wom

en

Age (years)Age (years)

**

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DemographicsDemographics In 2003 there were 4,000,000In 2003 there were 4,000,000

postmenopausal Canadian women.postmenopausal Canadian women.

One woman will enter the menopauseOne woman will enter the menopause

every 10 seconds until 2015.every 10 seconds until 2015.

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Menopause: SymptomsMenopause: Symptoms Hot flashesHot flashes Night sweatsNight sweats Sleep disturbanceSleep disturbance Poor memoryPoor memory Poor concentrationPoor concentration Irritability/emotional labilityIrritability/emotional lability DepressionDepression

Bélisle S, et al. J Obstet Gynaecol Can 2006; 28(Suppl 1):S7-S94.Bélisle S, et al. J Obstet Gynaecol Can 2006; 28(Suppl 1):S7-S94.

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Menopause: SymptomsMenopause: Symptoms

FatigueFatigue Myalgias and athralgiasMyalgias and athralgias Urinary frequency and urgencyUrinary frequency and urgency Vaginal drynessVaginal dryness Diminished sexual drive and responseDiminished sexual drive and response

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Menopause symptomsMenopause symptoms

Vasomotor symptoms affect 60% to 80% of women Vasomotor symptoms affect 60% to 80% of women entering menopause.entering menopause.

60% of postmenopausal women experience hot 60% of postmenopausal women experience hot flashes for less than 7 years. Up to 15% report that flashes for less than 7 years. Up to 15% report that hot flashes persist for 15 years or more.hot flashes persist for 15 years or more.

Normally, the body maintains an optimal Normally, the body maintains an optimal temperature via the thermoneutral zone.temperature via the thermoneutral zone.

Metabolic activity is regulated through Metabolic activity is regulated through vasodilatation and sweating when overheated and vasodilatation and sweating when overheated and shivering when cold. shivering when cold.

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Menopause symptomsMenopause symptoms Postmenopausal women are thought to have Postmenopausal women are thought to have

narrowing of this “thermoneutral zone”. Small narrowing of this “thermoneutral zone”. Small changes in temperature can evoke the regulatory changes in temperature can evoke the regulatory response of sweating or shivering.response of sweating or shivering.

Risk factors for hot flashes : obesity, cigarette Risk factors for hot flashes : obesity, cigarette smoking, triggers (alcohol, warm ambient smoking, triggers (alcohol, warm ambient environment, hot drinks).environment, hot drinks).

These form the basis for lifestyle recommendations These form the basis for lifestyle recommendations to reduce vasomotor symptoms. to reduce vasomotor symptoms.

Freeman EW, Sherif K. Prevalence of hot flushes and night sweats around the world: a Freeman EW, Sherif K. Prevalence of hot flushes and night sweats around the world: a systematic review. Climacteric 2007;10:197–214.systematic review. Climacteric 2007;10:197–214.

Schwingl PJ, Hulka BS, Harlow SD. Risk factors for menopausal hot flashes. Obstet Gynecol Schwingl PJ, Hulka BS, Harlow SD. Risk factors for menopausal hot flashes. Obstet Gynecol 1994;84:29–341994;84:29–34..

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Symptomatic

Freedman RR. Am J Med 2005;118:124S-130S.

Upper threshold(Upper set point)

Lower threshold(Lower set point)

Sweating

Shivering

Thermo-neutral Zone(homeostatic

range)

Normal

Body temperature

Sweating

Shivering

CoreBody Temp

Menopause symptomsMenopause symptoms

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0

5

10

15

20

25

30

35

40

45

50

Number of Years Women Reported Having Hot Flashes

Nu

mb

er o

f S

ub

jec

tsSome Women Experience Hot Some Women Experience Hot

Flashes Flashes for a Few Months or Up to Many for a Few Months or Up to Many

YearsYears

Some Women Experience Hot Some Women Experience Hot Flashes Flashes

for a Few Months or Up to Many for a Few Months or Up to Many YearsYears

Data from a survey of 438 Data from a survey of 438 untreated women, aged 29 untreated women, aged 29

to 82 years, who to 82 years, who experienced hot flashes experienced hot flashes

regardlessregardlessof menopausal status.of menopausal status.

0 2 4 6 8 10 12 14 16 18 20 22 24 28 30 36 41

Adapted from Kronenberg F. Ann N Y Acad Sci 1990;592:52-86.

Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.

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Menopause: Health RisksMenopause: Health Risks

Low estrogen confers increased risks ofLow estrogen confers increased risks of : : Cardiovascular diseaseCardiovascular disease OsteoporosisOsteoporosis Colorectal cancerColorectal cancer Quality of life issues (vasomotor Quality of life issues (vasomotor

symptoms, sexual concerns, symptoms, sexual concerns, depression, cognitive decline)depression, cognitive decline)

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Lifestyle Counselling : Perceptions of Lifestyle Counselling : Perceptions of Canadian WomenCanadian Women

0 10 20 30 40 50

41%

27%

16%

8%2%

6%

Causes of Death

Breast Cancer

Cancer (non-specific)

Heart / BP / Stroke

Lung Cancer

Uterine Cancer

Other/Don’t Know

Percentage

Cardiovascular Disease FactsCardiovascular Disease Facts

Menopause compounds the traditional CVD Menopause compounds the traditional CVD risk factors:risk factors:

Central adiposityCentral adiposity Glucose intoleranceGlucose intolerance DyslipidemiaDyslipidemia Endothelial dysfunctionEndothelial dysfunction

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Cardiovascular Disease FactsCardiovascular Disease Facts

#1 cause of death#1 cause of death Onset 10-15 years after menopause (Later in life)Onset 10-15 years after menopause (Later in life) By age 75 : 1/3 of women are affected by CVDBy age 75 : 1/3 of women are affected by CVD 1/6 of women die from CVD1/6 of women die from CVD Menopause has Menopause has no direct effect no direct effect on plasma glucose on plasma glucose

and insulinand insulinMain effects of estrogen defficiency is on lipid profileMain effects of estrogen defficiency is on lipid profile Cholesterol changes Cholesterol changes HDL-C HDL-C LDL-CLDL-C Vascular effects as a result of dyslipidemiaVascular effects as a result of dyslipidemia - - plaque development plaque development

- - ability to dilate ability to dilate

LIPID CHANGESLIPID CHANGESIn the late perimenopause and the early In the late perimenopause and the early menopause (within a year), the following menopause (within a year), the following changes occur.changes occur.LDL increases (6-10 %)LDL increases (6-10 %)Triglycerides increase (3-11%)Triglycerides increase (3-11%)Apolipoprotein B increasesApolipoprotein B increasesTotal cholesterol increases (mainly from LDL Total cholesterol increases (mainly from LDL increase)increase)HDL –variable 6 studies 6 % HDL –variable 6 studies 6 %

3 studies 8-15% 3 studies 8-15%

6 studies unchanged 6 studies unchanged 22

LIPID CHANGESLIPID CHANGES HDL depends on environmental factorsHDL depends on environmental factors Lack of exercise (decreases HDL) Lack of exercise (decreases HDL) Alcohol consumption ( increases HDL)Alcohol consumption ( increases HDL) Increased BMI ( decreases HDL) Increased BMI ( decreases HDL) No genetic factorsNo genetic factors

Increased Total cholesterol /HDL ratio Increased Total cholesterol /HDL ratio resulting in faster arterial agingresulting in faster arterial aging

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Normal bone Osteoporosis

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strengthcompromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone qualitybone density and bone quality..

Definition of OsteoporosisDefinition of Osteoporosis

NIH Consensus Development Panel on Osteoporosis. JAMA 2001

Age and Fracture Risk

The hip, spine and wrist are the most common sites of fracture in osteoporosis.

A 50 year old woman has a 40% chance of any fracture over her lifetime.

Major Risk Factors (1 or Major Risk Factors (1 or more)more)

Major Risk Factors (1 or Major Risk Factors (1 or more)more) Age >65 yearsAge >65 years

Hypogonadism (no estrogen-Hypogonadism (no estrogen-menopause)menopause)

Family Hx of osteoporosisFamily Hx of osteoporosis Vertebral fractureVertebral fracture Fragility fracture under age Fragility fracture under age

4040 Propensity to fallPropensity to fall Early menopause (<45)Early menopause (<45) Other (glucocorticoid-steroid Other (glucocorticoid-steroid

therapy therapy >3 months, malabsorption >3 months, malabsorption etc.)etc.)

Minor Risk Factors (2 or Minor Risk Factors (2 or more)more)

Minor Risk Factors (2 or Minor Risk Factors (2 or more)more)

SmokerSmoker Weight less than 57 kgs (125 lbs)Weight less than 57 kgs (125 lbs) Excessive intake of caffeine or Excessive intake of caffeine or

alcoholalcohol Past clinical hyperthyroidismPast clinical hyperthyroidism Anticonvulsant therapyAnticonvulsant therapy Low calcium intakeLow calcium intake Rheumatoid arthritisRheumatoid arthritis Chronic heparin therapyChronic heparin therapy

Prevention of Prevention of Osteoporosis Osteoporosis

CalciumCalciumCalciumCalcium• Essential mineral for good bone healthEssential mineral for good bone health• Recommended intakes (combination of diet Recommended intakes (combination of diet

and supplements):and supplements):• Peri-menopause - 1000 mg/dPeri-menopause - 1000 mg/d• Post-menopause - 1200 mg/d Post-menopause - 1200 mg/d

• Can be taken in divided doses Can be taken in divided doses • Food sources: dairy, canned fish,Food sources: dairy, canned fish,

nuts, fortified foods, some leafy greensnuts, fortified foods, some leafy greens• Calcium therapy alone is insufficient Calcium therapy alone is insufficient

in patients at high risk for fracturein patients at high risk for fracture

Vitamin DVitamin DVitamin DVitamin D• Important for maintenance of Important for maintenance of

bone healthbone health• Most recommend intake of 1,000 Most recommend intake of 1,000

IU/d of Vitamin D3IU/d of Vitamin D3• Deficiency common due to Deficiency common due to

limited sun exposure / use of limited sun exposure / use of sunscreensunscreen

• Food sources: fortified milk, soy Food sources: fortified milk, soy beverages, and margarine, fish, beverages, and margarine, fish, liver, egg yolkliver, egg yolk

• Sun exposure 20 min / day Sun exposure 20 min / day

Physical Activity

Modified from Drinkwater BL. 2nd World Congress on Aging Male, Geneva, 2000.

Exercise and balance training

Improved coordination

Better balance

Greater strength

Less chances of falling

Less fractures

Less damage from fall

Exercise and Balance Exercise and Balance Training: Training:

Effect on Falls and Effect on Falls and FracturesFractures

Exercise and Balance Exercise and Balance Training: Training:

Effect on Falls and Effect on Falls and FracturesFractures

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Case StudyCase Study

Mrs. M is a 54-year-old womanMrs. M is a 54-year-old woman Her last menstrual period was 18 Her last menstrual period was 18

months ago.months ago. She presents to your office She presents to your office

complaining of unbearable hot complaining of unbearable hot flashes.flashes.

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HistoryHistory Establish that this is Establish that this is aa symptom of symptom of

menopause and ask about menopause and ask about presence of other presence of other symptoms of menopausesymptoms of menopause..

Assess the Assess the severity of symptomsseverity of symptoms and the and the impactimpact on her function and quality of life. on her function and quality of life.

Obtain information regarding Obtain information regarding past and past and current therapiescurrent therapies used to alleviate symptoms used to alleviate symptoms and effectiveness (and effectiveness (i.e i.e herbals, etc).herbals, etc).

Obtain personal and family histories to Obtain personal and family histories to investigate for investigate for risk factorsrisk factors (CVD, (CVD, osteoporosis, cancers). osteoporosis, cancers).

Establish any Establish any contraindicationscontraindications to HT. to HT.

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Contraindications to Hormonal Contraindications to Hormonal therapytherapy

Hormone- dependent cancers (breast Hormone- dependent cancers (breast cancer, endometrial cancer) cancer, endometrial cancer)

Active or recent arterial Active or recent arterial thromboembolic disease (MI, Angina)thromboembolic disease (MI, Angina)

Venous thromboembolism, PEVenous thromboembolism, PE Severe active liver diseaseSevere active liver disease Uninvestigated abnormal uterine Uninvestigated abnormal uterine

bleedingbleeding

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Physical ExamPhysical Exam

General : Blood pressure, Weight, BMI General : Blood pressure, Weight, BMI Cardiac / respiratory examCardiac / respiratory exam Breast ExamBreast Exam Abdominal examAbdominal exam PAP test and pelvic exam : looking for PAP test and pelvic exam : looking for

pelvic masses, signs of vulvo-vaginal pelvic masses, signs of vulvo-vaginal atrophy, decreased vaginal calibre. atrophy, decreased vaginal calibre.

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InvestigationsInvestigations

Hormonal profile : FSH, LH, E2Hormonal profile : FSH, LH, E2 Fasting lipids/glucoseFasting lipids/glucose Pelvic ultrasound (if indicated)Pelvic ultrasound (if indicated) MammogramMammogram Bone mineral density (BMD)Bone mineral density (BMD)

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Counselling - Counselling - Preventive Care for Preventive Care for Menopausal WomenMenopausal Women

Monitor BP, glucose, lipid profile, thyroid Monitor BP, glucose, lipid profile, thyroid functionfunction

Regular Pap smearRegular Pap smear Regular breast exam (provincial screening Regular breast exam (provincial screening

program- OBSP)program- OBSP) Mammogram Mammogram Colorectal cancer screeningColorectal cancer screening Selective bone density testingSelective bone density testing Flu shot Flu shot Safe sexSafe sex Fall-proofing recommendations for seniorsFall-proofing recommendations for seniors

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First Line Health First Line Health Promotion/Promotion/

Disease Prevention Disease Prevention MeasuresMeasures

Exercise CalciumVitamin D

Smoking Cessation

ModerationofAlcoholIntake

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Treatment of vasomotor Treatment of vasomotor symptomssymptoms

Systemic Hormonal therapySystemic Hormonal therapy Proven efficacy to treat menopausal Proven efficacy to treat menopausal

symptoms.symptoms. Not meant to replace endogenous Not meant to replace endogenous

hormone.hormone. Approved for the symptomatic relief of hot Approved for the symptomatic relief of hot

flashes affecting quality of life.flashes affecting quality of life. Other benefits include improvement of Other benefits include improvement of

vaginal dryness and prevention of vaginal dryness and prevention of osteoporosis.osteoporosis.

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SOGC Guidelines : VMSSOGC Guidelines : VMS

1. 1. Lifestyle modifications, including reducing Lifestyle modifications, including reducing core body temperature, regular exercise, core body temperature, regular exercise, weight management, smoking cessation, and weight management, smoking cessation, and avoidance of known triggers such as hot avoidance of known triggers such as hot drinks and alcohol may be recommended to drinks and alcohol may be recommended to reduce mild vasomotor symptoms. (IC)reduce mild vasomotor symptoms. (IC)

2. Health care providers should offer 2. Health care providers should offer HTHT (estrogen alone or EPT) as the (estrogen alone or EPT) as the most effective most effective therapytherapy for the medical management of for the medical management of menopausal symptoms. (IA)menopausal symptoms. (IA)

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3. Progestins alone or low-dose oral contraceptives 3. Progestins alone or low-dose oral contraceptives can be offered as alternatives for the relief of can be offered as alternatives for the relief of menopausal symptoms during the menopausal menopausal symptoms during the menopausal transition. (IA)transition. (IA)

4. 4. Nonhormonal prescription therapiesNonhormonal prescription therapies, including , including treatment with certain antidepressant agents treatment with certain antidepressant agents (venlafaxine), gabapentin, clonidine, and bellergal, (venlafaxine), gabapentin, clonidine, and bellergal, may afford some relief from hot flashes but have may afford some relief from hot flashes but have their own side effects. their own side effects.

These alternatives can be considered when HT is These alternatives can be considered when HT is contraindicated or not desiredcontraindicated or not desired. (IB). (IB)

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There is There is limited evidence of benefitlimited evidence of benefit of most complementary and of most complementary and alternative approaches for the management of hot flashes. alternative approaches for the management of hot flashes. Without good evidence for effectiveness, and in the face of Without good evidence for effectiveness, and in the face of minimal data on safety, these approaches minimal data on safety, these approaches should be advised should be advised with cautionwith caution.(IB).(IB)

Women should be advised that, until January 2004, most Women should be advised that, until January 2004, most natural health products were introduced into Canada as “food natural health products were introduced into Canada as “food products” and did not fall under the regulatory requirements products” and did not fall under the regulatory requirements for pharmaceutical products. As such, most have not been for pharmaceutical products. As such, most have not been rigorously tested for the treatment of moderate to severe hot rigorously tested for the treatment of moderate to severe hot flashes, and many lack evidence of efficacy and safety. (IB)flashes, and many lack evidence of efficacy and safety. (IB)

SOGC. J Obstet Gynaecol Can 2009; 31(Suppl 1):S1-S46.SOGC. J Obstet Gynaecol Can 2009; 31(Suppl 1):S1-S46.

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SOGC recommendations : VMSSOGC recommendations : VMS

Several recent systematic reviews have examined complimentary Several recent systematic reviews have examined complimentary options for treatment of moderate to severe vasomotor options for treatment of moderate to severe vasomotor symptoms.symptoms.

None of these found any single complementary therapy to have None of these found any single complementary therapy to have proven efficacy for moderate to severe hot flashes.proven efficacy for moderate to severe hot flashes.

A direct head-to-head comparison of HT versus black cohosh, A direct head-to-head comparison of HT versus black cohosh, soy, or multibotanicals showed soy, or multibotanicals showed only HT to have an effect greater only HT to have an effect greater than that of placebo.than that of placebo.

Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh,multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern menopause with black cohosh,multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006;145:869–79.Med 2006;145:869–79.

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HT and Cardiovascular disease risksHT and Cardiovascular disease risks

Mrs. M is concerned about cardiac Mrs. M is concerned about cardiac risks associated with HRTrisks associated with HRT ““I heard a big study showed more I heard a big study showed more

heart attacks in people taking heart attacks in people taking hormones”hormones”

How do you address this concern? How do you address this concern?

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Women’s Health Initiative (WHI)Women’s Health Initiative (WHI)

Asymptomatic Asymptomatic patients, average age 63 years, patients, average age 63 years, 1/3 > 70 years, with high incidence of diabetes and untreated 1/3 > 70 years, with high incidence of diabetes and untreated hypertension.hypertension.

Study used Study used conjugated estrogens (0.625 mg CES and 2.5 mg of conjugated estrogens (0.625 mg CES and 2.5 mg of medroxyprogesterone acetate = provera).medroxyprogesterone acetate = provera).

Reanalysis actually showed that only a small subgroup of Reanalysis actually showed that only a small subgroup of smokers smokers had increased risk of cardiac events.had increased risk of cardiac events.

The conclusion should have been: The conclusion should have been: don’t use these medications in don’t use these medications in elderly asymptomatic women.elderly asymptomatic women.

This set back female healthcare by a decade.This set back female healthcare by a decade.Rossouw JE, et al. JAMA 2002; 288(3):321-33.

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Consequences of the Initial WHI ReportsConsequences of the Initial WHI Reports Many doctors and patients became Many doctors and patients became fearful of HT.fearful of HT.

Many doctors advised discontinuation of HRT and 50% of Many doctors advised discontinuation of HRT and 50% of users stopped.users stopped.

This fueled the multibillion-dollar market in alternate and This fueled the multibillion-dollar market in alternate and complementary products.complementary products.

As many as 25% of those who stopped HT returned to their As many as 25% of those who stopped HT returned to their doctors for “permission” to resume treatments.doctors for “permission” to resume treatments.

A new generation of women have become hormone savvy and A new generation of women have become hormone savvy and want to participate in their menopause therapy choices.want to participate in their menopause therapy choices.

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Current Evidence: HT and CVD ParadoxCurrent Evidence: HT and CVD Paradox

HT within five years of removal of the ovaries HT within five years of removal of the ovaries or in premature ovarian failure is or in premature ovarian failure is cardioprotective.cardioprotective.

HT should be offered to women with HT should be offered to women with premature ovarian failure or early menopause premature ovarian failure or early menopause (IA), and it can be recommended until the age (IA), and it can be recommended until the age of natural menopause (IIIC)-2006.of natural menopause (IIIC)-2006.

Estrogen therapy can be offered to women Estrogen therapy can be offered to women who have undergone surgical menopause for who have undergone surgical menopause for the treatment of endometriosis. (IA)-2006the treatment of endometriosis. (IA)-2006

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Current Evidence : HT and CVD Current Evidence : HT and CVD ParadoxParadox

There is There is no no convincing evidence for an increase in convincing evidence for an increase in the risk of the risk of cardiovascular disease cardiovascular disease in in newly newly menopausalmenopausal women starting hormone therapy; women starting hormone therapy; women should be reassured about this ---- (New in women should be reassured about this ---- (New in SOGC 2009).SOGC 2009).

Is HT cardioprotective in newly menopausal Is HT cardioprotective in newly menopausal women?women?

We will probably never get the answer: to We will probably never get the answer: to demonstrate a 10% reduction in cardiovascular demonstrate a 10% reduction in cardiovascular mortality in women aged 55 to 59 years, 186,000 mortality in women aged 55 to 59 years, 186,000 women have to remain compliant with hormones women have to remain compliant with hormones or placebo for 10 years.or placebo for 10 years.

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Critical window hypothesisCritical window hypothesis

Suggest that the use of HT at the onset of menopause Suggest that the use of HT at the onset of menopause could be cardioprotective whereas later initiation could could be cardioprotective whereas later initiation could cause adverse coronary events as seen in the WHIcause adverse coronary events as seen in the WHI

This theory suggests that the prothrombotic or plaque-This theory suggests that the prothrombotic or plaque-destabilizing effects of HT in women with established destabilizing effects of HT in women with established CAD may account for an initial increase in the incidence CAD may account for an initial increase in the incidence of coronary artery events in older women, but that the of coronary artery events in older women, but that the healthy coronary arteries of younger women benefit healthy coronary arteries of younger women benefit from the anti-atherogenic effects of estrogen.from the anti-atherogenic effects of estrogen.

Lobo RA. Evaluation of cardiovascular event rates with Lobo RA. Evaluation of cardiovascular event rates with hormonal therapy in healthy, early menopausal women: results hormonal therapy in healthy, early menopausal women: results from two large clinical trials. Arch Intern Med 2004;164:482–4.from two large clinical trials. Arch Intern Med 2004;164:482–4.

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HT and VTE risksHT and VTE risks

Mrs. M is concerned about VTE Mrs. M is concerned about VTE risk associated with HRTrisk associated with HRT““I read something about a risk of blood I read something about a risk of blood

clots when taking hormones”clots when taking hormones”


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HT and VTE RisksHT and VTE Risks

HRT very slightly increases the risk of a HRT very slightly increases the risk of a blood clot (2-3 additional cases per 10,000 blood clot (2-3 additional cases per 10,000 users).users).

The risk is greatest in the first year of use.The risk is greatest in the first year of use.

In the WHI the HR was 4.0 in year 1 and fell to In the WHI the HR was 4.0 in year 1 and fell to 1.04 by year 6.1.04 by year 6.

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HT and VTE RisksHT and VTE Risks

Age is a much greater risk factor: compared Age is a much greater risk factor: compared to a baseline at 50-59 years, risk doubles at to a baseline at 50-59 years, risk doubles at 60-69 years and quadruples at 70-79 years.60-69 years and quadruples at 70-79 years.

Risk reduced with Risk reduced with lower doseslower doses and and transdermal transdermal estrogen.estrogen.

Cushman M, Kuller LH, Prentice R, et al. JAMA 2004;292:1573-80.Cushman M, Kuller LH, Prentice R, et al. JAMA 2004;292:1573-80.Curb JD, Prentice RL, Bray PF, et al.Curb JD, Prentice RL, Bray PF, et al. Arch Intern Med 2006; 166:772-80. Arch Intern Med 2006; 166:772-80.Silverstein MD, Heit JA, Mohr DN, Silverstein MD, Heit JA, Mohr DN, et al.et al. Arch Intern Med 1998; 158:585-93. Arch Intern Med 1998; 158:585-93.Canonico M, Oger E, Plu-Bureau G, et al. Circulation 2007; 115(7):840-5.Canonico M, Oger E, Plu-Bureau G, et al. Circulation 2007; 115(7):840-5.

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HT and StrokeHT and Stroke

To reduce the risk of To reduce the risk of stroke stroke in women in women taking HT, risk factors should be taking HT, risk factors should be addressed.addressed.

Use the Use the lowest effective doselowest effective dose, but no , but no absolute time limit.absolute time limit.

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HT and breast cancerHT and breast cancer

Mrs. M is concerned about breast-cancer risk Mrs. M is concerned about breast-cancer risk associated with HT.associated with HT.

““I read something about the risk of breast I read something about the risk of breast cancer in women taking hormones”cancer in women taking hormones”


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HT and Breast CancerHT and Breast Cancer Health care providers should periodically review the Health care providers should periodically review the

risks and benefits of prescribing HT to a menopausal risks and benefits of prescribing HT to a menopausal woman in light of the association between duration woman in light of the association between duration of use and breast cancer risk. (IA) of use and breast cancer risk. (IA)

Health care providers may prescribe HT for Health care providers may prescribe HT for menopausal symptoms in women at increased risk menopausal symptoms in women at increased risk of breast cancer with appropriate counselling and of breast cancer with appropriate counselling and surveillance. (IA)surveillance. (IA)

Health care providers should clearly discuss the Health care providers should clearly discuss the uncertainty of risks associated with HT after a uncertainty of risks associated with HT after a diagnosis of breast cancer in women seeking diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB)treatment for distressing symptoms. (IB)

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HT and Breast Cancer RisksHT and Breast Cancer Risks

Lifetime exposure Lifetime exposure to hormones is linked to hormone-to hormones is linked to hormone-receptor-positive breast cancer; this risk is 4.6% for the receptor-positive breast cancer; this risk is 4.6% for the ages 50-70 years.ages 50-70 years.

Family history Family history is a separate risk.is a separate risk.

Factors such as Factors such as lack of exercise, gaining weight and lack of exercise, gaining weight and alcohol consumption alcohol consumption raise the risk; 1/3 of postmenopausal raise the risk; 1/3 of postmenopausal breast cancers could be avoided by lifestyle modification.breast cancers could be avoided by lifestyle modification.

Sprague BL, Trentham-Dietz A, Egan KM, et al. Am J Epidemiol 2008; 168(4):404-11. Sprague BL, Trentham-Dietz A, Egan KM, et al. Am J Epidemiol 2008; 168(4):404-11.

Sprague BL, et al. Am J Epidemiol 2008; 168(4):404-11.

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Many studies indicate a small increased risk of breast Many studies indicate a small increased risk of breast cancer, with longer-term use of hormone therapycancer, with longer-term use of hormone therapy

WHI WHI study: CEE (0.625 mg) and MPA (2.5 mg)study: CEE (0.625 mg) and MPA (2.5 mg) 26% increased risk of breast cancer with treatment 26% increased risk of breast cancer with treatment

vs. placebo (8 additional cases per vs. placebo (8 additional cases per 10,000 person-years: absolute excess risk)10,000 person-years: absolute excess risk)

no increased risk with unopposed estrogen*no increased risk with unopposed estrogen*

Rossouw JE, Anderson GL, Prentice RL, et al.JAMA 2002; 288:321-33.Rossouw JE, Anderson GL, Prentice RL, et al.JAMA 2002; 288:321-33.

Anderson GL, Limacher M, Assaf AR, et al. JAMA 2004; 291(14):1701-12.Anderson GL, Limacher M, Assaf AR, et al. JAMA 2004; 291(14):1701-12.2..

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WHI study finding of a 26% increased risk “is WHI study finding of a 26% increased risk “is meaningless without information on the background meaningless without information on the background risk of breast cancer by age group.” risk of breast cancer by age group.”

Risk translated into an absolute increased risk of 8 Risk translated into an absolute increased risk of 8 additional cases per 10,000 HT users per year in the additional cases per 10,000 HT users per year in the older population of the WHI. older population of the WHI.

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HT and Breast Cancer RisksHT and Breast Cancer RisksSOGC 2009SOGC 2009 Health care providers should periodically review the Health care providers should periodically review the

risks and benefits of prescribing HT to a menopausal risks and benefits of prescribing HT to a menopausal woman in light of the association between duration woman in light of the association between duration of use and breast cancer risk. (IA)of use and breast cancer risk. (IA)

Health care providers may prescribe HT for Health care providers may prescribe HT for

menopausal symptoms in women at increased risk menopausal symptoms in women at increased risk of breast cancer with appropriate counselling and of breast cancer with appropriate counselling and surveillance. (IA)surveillance. (IA)

Health care providers should clearly discuss the Health care providers should clearly discuss the uncertainty of risks associated with HT after a uncertainty of risks associated with HT after a diagnosis of breast cancer in women seeking diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB)treatment for distressing symptoms. (IB)

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Other Risk Factors for Breast Cancer with Other Risk Factors for Breast Cancer with Hazard Ratios of Approximately 1.3Hazard Ratios of Approximately 1.3

Early menarcheEarly menarche Late menopauseLate menopause Postmenopausal obesityPostmenopausal obesity First pregnancy after age 30 yearsFirst pregnancy after age 30 years Not breastfeedingNot breastfeeding No regular exerciseNo regular exercise Excess alcoholExcess alcohol

SOGC. J Obstet Gynaecol Can 2009; 31(Suppl 1):S1-S46.

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HT and Breast Cancer RisksHT and Breast Cancer RisksBreast densityBreast density

Increased breast density has been found to be an independent Increased breast density has been found to be an independent risk factor for breast cancer.risk factor for breast cancer.

Studies have indicated a 15% to 20% decrease in Studies have indicated a 15% to 20% decrease in mammographic sensitivity in hormone users who have dense mammographic sensitivity in hormone users who have dense breasts.breasts.

Women receiving postmenopausal HT in the WHI were found to Women receiving postmenopausal HT in the WHI were found to have increased breast density and a greater frequency of have increased breast density and a greater frequency of abnormal mammograms compared with those receiving abnormal mammograms compared with those receiving placebo.placebo.

Even though breast density can be increased by the use of Even though breast density can be increased by the use of estrogen with a progestin, it has never been shown that an estrogen with a progestin, it has never been shown that an acquired increase in density, as in hormone treatment, acquired increase in density, as in hormone treatment, increases breast cancer risk.increases breast cancer risk.

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Urogenital atrophy: Urogenital atrophy: Time Does Not Time Does Not Heal Heal

Vaginal drynessVaginal dryness Often a first sign of menopauseOften a first sign of menopause Progressive with timeProgressive with time Experienced by > 50% of womenExperienced by > 50% of women

DiscomfortDiscomfort Dyspareunia (pain with intercourse)Dyspareunia (pain with intercourse) BleedingBleeding Post-coital bleeding / dischargePost-coital bleeding / discharge Urinary urgency / frequency Urinary urgency / frequency Urinary incontinenceUrinary incontinence

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Approximately 4 million postmenopausal Approximately 4 million postmenopausal Canadian women Canadian women 11

1.6 million (40%) have urogenital atrophy 1.6 million (40%) have urogenital atrophy 22

Only 1 in 5 will talk to their doctor about it Only 1 in 5 will talk to their doctor about it 33

1.SOGC Consensus Conference on Menopause and Osteoporosis, 2002 Update.2.Johnston S, et al. SOGC Conference Highlights. June 2003.

3.Pandit L, et al. Am J Med Sci 1997;314(4):228-31.

Urogenital Atrophy: An unspoken concernUrogenital Atrophy:

An unspoken concern

Unlike VMS, urogenital atrophy will progressively worsen with timeUnlike VMS, urogenital atrophy will progressively worsen with time

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Urogenital AtrophyUrogenital Atrophy

Local Vaginal estrogenLocal Vaginal estrogen Treatment of choice for vaginal atrophy in Treatment of choice for vaginal atrophy in

the absence of bothersome vasomotor the absence of bothersome vasomotor symptoms.symptoms.

Available as :Available as : Cream - premarin vaginal cream, estragyn Cream - premarin vaginal cream, estragyn

cream. (2-3x a week)cream. (2-3x a week) Vaginal suppository – Vagifem (2-3x a Vaginal suppository – Vagifem (2-3x a

week)week) Vaginal ring – estring (q 3 months)Vaginal ring – estring (q 3 months)

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Bioidentical HTBioidentical HT

Mrs. M is curious about the issue of Mrs. M is curious about the issue of bio-identical hormonesbio-identical hormones ““I saw a television show during I saw a television show during

which some beauty icons said bio-which some beauty icons said bio-identical hormones are much better identical hormones are much better and saferand safer””

How do you address this? How do you address this?

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Bio-identical hormonesBio-identical hormones To scientists and health care providers, bio-identical To scientists and health care providers, bio-identical

means chemically identical to the hormones means chemically identical to the hormones produced by women (mainly the ovaries)--- estrone, produced by women (mainly the ovaries)--- estrone, 17B- estradiol, estriol, progesterone and 17B- estradiol, estriol, progesterone and testosterone.testosterone.

Bio-identical hormonal therapy means medication Bio-identical hormonal therapy means medication that provides one or more of these hormones as the that provides one or more of these hormones as the active ingredient.active ingredient.

Bioidentical hormones are available as Bioidentical hormones are available as (i) Government approved, well tested, commercial, (i) Government approved, well tested, commercial,

brand name prescription drugs.brand name prescription drugs. (ii) Custom-compounded formulations. (ii) Custom-compounded formulations.

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Bio-identical hormonesBio-identical hormones

Prescription bio-identicals includePrescription bio-identicals include

(i) 17B-estradiol preparations- oral (i) 17B-estradiol preparations- oral estrace, estrace vaginal cream (U.S.A), estrace, estrace vaginal cream (U.S.A), all transdermal preparations, estring.all transdermal preparations, estring.

(ii) Progesterone capsules—micronized (ii) Progesterone capsules—micronized progesterone (prometrium).progesterone (prometrium).

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Custom- compounded formulationsCustom- compounded formulations• Not tested for safety and efficacy yet being Not tested for safety and efficacy yet being

offered as safer and more effective offered as safer and more effective alternatives to government approved alternatives to government approved medications.medications.

• Batch to batch variation ?? sterility.Batch to batch variation ?? sterility.

• Expensive and not reimbursed by third party Expensive and not reimbursed by third party payers.payers.

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Bio-identical hormonesBio-identical hormones Custom compounded preparations often Custom compounded preparations often

include estriol (10% activity of E2). include estriol (10% activity of E2).

Tri-estrogen mixture: 80% estriol, 10% Tri-estrogen mixture: 80% estriol, 10% estrone, 10% estradiol (promoted as not estrone, 10% estradiol (promoted as not increasing the risk of breast cancer---BUT increasing the risk of breast cancer---BUT estriol can still have stimulatory effects on estriol can still have stimulatory effects on the breast and endometium).the breast and endometium).

Topical progesterone preparations have not Topical progesterone preparations have not been shown to counter the stimulatory been shown to counter the stimulatory effects of estrogen on the uterus.effects of estrogen on the uterus.

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• Natural is not synonymous with bio-identical. Often Natural is not synonymous with bio-identical. Often used to refer to hormonal preparations of plant used to refer to hormonal preparations of plant origin which may have undergone multiple chemical origin which may have undergone multiple chemical reactions during synthesis.reactions during synthesis.

• Salivary hormone testing is not proven to be reliable Salivary hormone testing is not proven to be reliable and accurate and there is no such thing as the “right and accurate and there is no such thing as the “right amount of hormones”. A woman’s physical comfort amount of hormones”. A woman’s physical comfort may not be related to her absolute hormonal status.may not be related to her absolute hormonal status.

• The North American Menopause Society ( NAMS) The North American Menopause Society ( NAMS) does not recommend custom- compounded does not recommend custom- compounded preparations over well tested government approved preparations over well tested government approved products.products.

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Routes of estrogen delivery

Mrs. M wants to know more about Mrs. M wants to know more about the different formulations of HRTthe different formulations of HRT ““On that same television show, they On that same television show, they

said that creams are better than pills. said that creams are better than pills. Is that true?”Is that true?”


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The Routes of Estrogen DeliveryThe Routes of Estrogen Delivery Oral estrogen has drawbacks:Oral estrogen has drawbacks:

raises raises fibrinogen and other coagulation factorsfibrinogen and other coagulation factors raises raises C-reactive proteinC-reactive protein raises raises triglycerides by 25%triglycerides by 25% raises raises sex-hormone-binding globulinsex-hormone-binding globulin

Transdermal estrogen Transdermal estrogen does not have these negative does not have these negative effectseffects

Transdermal estrogen is available as a Transdermal estrogen is available as a gel or patchgel or patch

Hirvonen E, Cacciatore B, Wahlström T, et al. Br J Obstet Gynaecol 1997; 104 (Suppl 16):26-31.Hirvonen E, Cacciatore B, Wahlström T, et al. Br J Obstet Gynaecol 1997; 104 (Suppl 16):26-31.

Hirvonen E, et al. Br J Obstet Gynaecol 1997; 104(Suppl 16):26-31.

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The Routes of Estrogen DeliveryThe Routes of Estrogen Delivery

Advantages of the Transdermal approachAdvantages of the Transdermal approach• Provides 17B estradiol structurally similar to Provides 17B estradiol structurally similar to

ovarian source (oral preparations also ovarian source (oral preparations also available).available).

• Avoids first pass effect on the liver. Avoids first pass effect on the liver. • Relatively stable plasma levels.Relatively stable plasma levels.• Permits measurement of serum estradiol in Permits measurement of serum estradiol in

cases of necessary dose adjustments.cases of necessary dose adjustments.

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Choice of specific HTChoice of specific HT

17-beta estradiol 17-beta estradiol is the principal naturally is the principal naturally occurring estrogen in femalesoccurring estrogen in females reductions in this hormone lead to the reductions in this hormone lead to the

symptoms of menopause, as well as to an symptoms of menopause, as well as to an increase in long-term health risks such as increase in long-term health risks such as heart disease, osteoporosis and bowel heart disease, osteoporosis and bowel cancer. cancer.

logically hormone therapy should be logically hormone therapy should be aimed at the aimed at the restoration of the bio-restoration of the bio-identical hormone.identical hormone.

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Mrs. M requests counseling Mrs. M requests counseling regarding regarding what specific type of what specific type of estrogen or progesteroneestrogen or progesterone she she should use.should use.


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Conjugated equine estrogen (CEE/premarin) Conjugated equine estrogen (CEE/premarin) is composed of more than 10 estrogens is composed of more than 10 estrogens largest component being estrone (45%). largest component being estrone (45%).

Pharmacologic effect is the sum of activity of Pharmacologic effect is the sum of activity of all the component estrogens.all the component estrogens.

The majority of component estrogens have The majority of component estrogens have never been identified.never been identified.

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Progestins are not Progesterone.Progestins are not Progesterone.

Progesterone Progesterone is the naturally occurring is the naturally occurring progestational agent in females; it is progestational agent in females; it is bio-bio-identical.identical.

Progestins are synthetic drugs Progestins are synthetic drugs used to used to mimic some of the effects of progesterone.mimic some of the effects of progesterone.

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HT summaryHT summary

Estrogen:Estrogen:

Use the lowest dose of Use the lowest dose of estrogen estrogen that alleviates that alleviates symptoms; this could be conjugated estrogen pill symptoms; this could be conjugated estrogen pill 0.3 mg, estradiol 0.5 mg, a 25 ug patch or estradiol 0.3 mg, estradiol 0.5 mg, a 25 ug patch or estradiol gel 1 metered dose. gel 1 metered dose.

Titrate Titrate the dose to the individual patient; the dose to the individual patient; symptom symptom relief relief is often a better indicator than blood levels.is often a better indicator than blood levels.

Commercially available gels and patches have better Commercially available gels and patches have better quality control quality control than compounded gels and creams than compounded gels and creams made by pharmacists.made by pharmacists.

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HT SummaryHT Summary

Progesterone:Progesterone:

Micronized progesterone Micronized progesterone is available commercially is available commercially with excellent quality control.with excellent quality control.

100 mg is the usual dose.100 mg is the usual dose.

Take at Take at bedtime on an empty stomach.bedtime on an empty stomach.

Progesterone cream not as well absorbed as oral Progesterone cream not as well absorbed as oral progesterone.progesterone.

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Key Points in Managing Key Points in Managing Menopausal SymptomsMenopausal Symptoms

Establish that patient’s symptoms are related to menopause.Establish that patient’s symptoms are related to menopause. Assess the impact on quality of life.Assess the impact on quality of life. Determine what treatments patient has tried before Determine what treatments patient has tried before

(herbals, etc.)(herbals, etc.) Look for any risk factors that make HT higher riskLook for any risk factors that make HT higher risk

advanced ageadvanced age DVTDVT CV diseaseCV disease breast cancer (personal or first degree relatives)breast cancer (personal or first degree relatives)

If HT is to be used, decide between oral and topical E2.If HT is to be used, decide between oral and topical E2. Decide which estrogen and which progesterone: lowest dose Decide which estrogen and which progesterone: lowest dose

to control symptoms.to control symptoms.

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THE ENDTHE END

THANK YOU.THANK YOU.

QUESTIONS ??QUESTIONS ??

1 menopause barbara sproule, pgy-5 university of ottawa the ottawa hospital

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