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Menopause
Georges El-Kehdy, MD

Definition : period of time marked by irregular menstrual


cycles that precedes menopause (menopause is the
permanent cessation of menses with loss of follicles)
Age of onset: 39-51y (average 46y)
Duration :2-8y (average 5y)
Hormonal changes
Inhibin is decreased
FSH is increased(>20mIU/ml), LH is normal
E2 remains normal or slightly elevated until 6-12months before
menopause

Fertility is reduced because of reduced quality of aging


follicles with < inhibin,>FSH and acceleration of follicular
loss

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Age : 44-56y with a median of 51y


Factors that decrease age of menopause
smoking, malnutrition, low BMI. high
altitude, previous hysterectomy or
endometrial ablation
Maternal age of menopause:+ correlation
Alcohol increases the age of menopause
No correlation with age of menarche or
parity

Hormonal Production

Absence of follicles
Decreased ovarian volume
Gonadotropins are increased
Androgens are decreased
Estrogens are decreased
Androgens/estrogens ratio is increased
with increased incidence of hirsutism

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GONADOTROPINS

FSH is increased 10-20 fold


LH is increased 3 fold
LH has a shorter half-life than FSH
FSH and LH continue to increase for 2
years then a slight and gradual decline
Elevation of gonadotropins has a
diagnostic value

ANDROGENS
Androstenedione
Production is decreased by 50%
Origin is mainly adrenal with minimal ovarian
DHEA and DHEAS
Production is decreased by 70%
Origin is adrenal
Testosterone
Production is decreased by 25%
Origin is ovarian
Ovarian production is increased compared with
premenopausal production
FSH stimulates ovarian stromal tissue

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ESTROGENS
Estrogen production is decreased
Estrone level is higher than estradiol level
E1=30-70pg/ml
E2=10-20pg/ml
Origin is from peripheral conversion by
aromatization of androstenedione to
estrone and than to estradiol

Impact of Estrogen Deprivation

Vasomotor symptoms
Atrophic changes
Psychophysiologic effects
Cognition and Alzheimer's disease
Cardiovascular disease
Osteoporosis

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Symptoms associated with the


menopause
Acute

Intermediate/late

Hot flushes

Dyspareunia

Night sweats

Loss of libido

Insomnia

Urethral syndrome

Anxiety/irritability

Vaginal atrophy

Memory loss

Cardiovascular disease

Poor concentration

Osteoporosis

Mood changes

Climacteric complaints
By menopausal status
Pre
Vasomotor symptoms

Peri

Depressive mood

Post

Anxiety/fears
Sleep problems
Sexual problems
Cognitive difficulties
0

20

40

60

80

100

Mean percentage of women

Hunter, 1988

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Vasomotor Symptoms
(VMS)
Thebeginningisasubjectivefeelingofintenseheat.
Theperceptionbeginsinthethermoregulatory
centerlocatedinthehypothalamus.
Nextisareddeningoftheskin,firstofthehead,and
neck,andthentheanteriorchest:vasodilatory
responsetodissipatetheheat.
Nextisincreaseinperspiration,evaporation,and
coolingphase.

Vasomotor Symptoms
(VMS)

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Temperature in VMS

Vasomotor Symptoms
(VMS)
Averageduration:23min
Averagefrequency:1every23hours
Intensity:variable
Severe:interfereswithactivity,oftenassociated
with profusesweating
Moderate:perceptiblebutdoesnotinterrupt
activity
Mild:transientrednessoftheskin

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Thermoregulation

EndocrinologyofVMS

DecreaseinEstrogens:+
LHpulses:?
OpioidergicSystem:?
NorEpinephrin:+,butinthebrain[measured
throughitsmetabolite3methoxy4
hydroxyphenylglycol(MHPG)]Adrenergic
Brainreceptor(modulatedbyEstrogen)

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Vasomotor Symptoms
(VMS)
The prevalence of hot flashes varies with culture and
ethnicity.
Some cultures do not have a word to describe VMS
Up to 75% of American women report them and 26% to
60% rate them as severe.
They peak around the final menstruation
One third of women in late reproductive age, and 20% to
30% of those in their 60s and 70s experience VMS

Hot Flushes May Continue


Years After Menopause
Ages 29 to 82 Years
50

Number of Subjects

45

Number of years women report having


hot flushes as estimated by a survey of 501
untreated women who experienced hot flushes

40
35
30
25
20
15
10
5
0

10

12

14

16

18

20

22

24

28

30

36

41

Years
Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.
Kronenberg F. Ann NY Acad Sci. 1990;592:52-86. Used with permission.

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Risk Factors for VMS

MENOPAUSE
Impact of estrogen deprivation
EFFECTS ON COGNITIVE FUNCTION
Decreased memory,decreased cognitive
function and increased incidence of
Alzheimer disease are mainly in relation
with aging
Estrogen deprivation might have a role
because ERT might improve these effects
by protection of CNS cells

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MENOPAUSE
Impact of estrogen deprivation
PSYCO-PHYSIOLOGIC EFFECTS
Depression is not increased with
menopause
Emotional stability is disrupted by poor
sleep pattern which gets worse with aging
and menopause
HRT is indicated for severe hot flushes

MENOPAUSE
Impact of estrogen deprivation
CARDIOVASCULAR DISEASE
Risk of coronary heart disease
CHD is one of the leading causes of death in
women following cancer
Risk of CHD is over 3.5 times in men that of
women
With increasing age this advantage is gradually
lost (role of estrogen deprivation)
Lipid profile changes
HDL cholesterol is higher in women then in men
and does not change with menopause
LDL cholesterol is lower in females than in males
but increases after the menopause

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MENOPAUSE
Impact of estrogen deprivation
OSTEOPOROSIS

Bone remodeling is a constant process of bone


resorption and formation
Osteoporosis is the decreased bone mass with
micro architectural deterioration of bone tissue
leading to bone fragility
Estrogen deficiency is associated with an increased
responsiveness of bone to parathormone then an
increased osteoclastic activity leading to
osteoporosis
Risk of fracture depends on bone mass reached at
maturity(20years) and bone loss after menopause
After menopause there is an acceleration of bone
loss.

MENOPAUSE
Hormonal Replacement
Therapy (HRT)
TRADITIONAL INDICATIONS OF HORMONAL
REPLACEMENT THERAPY

Menopausal symptoms
Prevention of:
Primary and secondary coronary heart
disease (CHD)
Osteoporosis
Alzheimer disease

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MENOPAUSE
Hormonal Replacement
Therapy (HRT)
QUESTIONS ABOUT HRT
How effective in CHD and osteoporosis
What is the risk of breast cancer
What is the risk of thrombo-embolic
disease

MENOPAUSE
Hormonal Replacement
Therapy (HRT)

PREVIOUS STUDIES

Observational and epidemiologic

Results are conflicting

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MENOPAUSE
Hormonal Replacement
Therapy (HRT)
RECENT STUDIES
Meta-analysis
RCT: Randomized
Controlled
Trials

MENOPAUSE
Hormonal Replacement
Therapy (HRT)
UPDATES ON HRT

Protection against CHD


Risk of breast cancer
Risk of thrombo-embolic events
Decisions for HRT

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MENOPAUSE
Hormonal Replacement
Therapy (HRT)

Protection against CHD


Observational epidemiologic
Results
50% reduced risk of CHD
37% reduced mortality of CHD

MENOPAUSE
HRT
Protection against CHD
Impact of lipid profile

LDL-cholesterol

decreased

HDL-cholesterol

increased

Triglycerides

increased

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Protection against CHD


Secondary prevention of CHD
Heart and Estrogen/progestin Replacement
Study,HRS(1998)

Participants: 2763 women with pre-existing


CHD
and a mean age of 66.7years
Two groups:
1- Treated group with CEE 0.625mg
MPA 2.5mg
2- Placebo group
Duration of the study : 4.1years

Protection against CHD


Secondary prevention of CHD

HRS: results and conclusions

HRT did not reduce the overall rate of CHD


events
HRT increased the CHD events during the
first two years
HRT should not be used for secondary
prevention of CHD

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Protection against CHD


Secondary prevention of CHD
HRS II (2002)

Participants: same of HERS with additional


2.7years follow-up
Objective: to determine if the reduction in
CHD events observed in the later years of
HERS persisted
Results: after 6.8years HRT did not reduce
the risk of CHD events in women with preexisting CHD

Protection against CHD

Primary prevention of CHD


Womens Health Initiative Trial(WHI2002)
Participants: 16608 healthy women, age 5079
Two randomized groups:
Treated group with CEE0.625 and MPA 2.5
Placebo group

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Protection against CHD


Primary prevention of CHD
WHI Trial results
HRT increased the risk of CHD by 29%in
healthy menopaused women (37
versus30per 10 000 women)
Absolute risk per 10 000 womenyears=7CHD events
Conclusion: HRT should not be used for
primary prevention of CHD

Risk of breast cancer


Observational and epidemiologic studies

1990: prospective study from Sweden


showed a slightly increased risk of breast
cancer
1995: Iowa Womens Health Study
showed no increased risk of breast cancer

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Risk of breast cancer


Observational and epidemiologic studies
The Nurses Health Study (1995)

Risk of breast cancer


Estrogens in
past users
Estrogens in
current users
Progestogens
added

Not increased
Increased (RR=1.46)
Not decreased

Risk of breast cancer


Observational and epidemiologic studies
Meta-analysis: Worlds literature (1997)

Risk of breast cancer is increased in


menopaused women on HRT
Risk increases with duration of use : after
5years the RR=1.35
Risk of breast cancer is reduced after
cessation of HRT and disappears after 5
years

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Risk of breast cancer


Conclusion of previous studies

Results are discordant


Trend: increased risk of breast cancer with
HRT
Need for controlled randomized studies

Risk of breast cancer


WHI study results

HRT increased the risk of breast cancer by


26% (38 versus 30 per 10 000 women )
Absolute excess risk per 10 000 womenyears: 8 cases of breast cancer
The risk of breast cancer is significantly
increased after 4 years of HRT use

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RISK OF THROMBO-EMBOLIC EVENTS


3

relative risk

2.5
2
HERS
HERS II

1.5
1
0.5
0
4.00

5.00

6.00

years

RISK OF THROMBOEMBOLIC EVENTS


WHI study
HRT increased by 100% the risk of thromboembolism( RR=2.13 )
Absolute excess risk per 10 000women per
year=8 events
HRT increased the risk of stroke by 41% (29
versus 21 per 10 000)

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CONCLUSIONS
Risks of HRT
2.5

relative risk

2
1.5

TE
CHD
Breast K

1
0.5
0

CONCLUSIONS
Benefits of HRT

Treatment of menopausal symptoms


Prevention of osteoporosis
Decreased risk of colorectal cancer
Decreased risk of endometrial cancer

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CONCLUSIONS
Decisions for HRT
Dont start HRT if menopausal symptoms are
absent
Start HRT if menopausal symptoms are
affection the quality of life
Resume HRT if menopausal symptoms
reappear
Discontinue HRT if no menopausal
symptoms and use alternatives for
osteoporosis prevention or treatment

Definition of QOL
Global sense of self-satisfaction
Sense of well-being
Patients perception of her interest in life
Maintaining satisfactory interpersonal
relationships
Perception of physical and psychological
wellness
Satisfaction with position in life in the context
of culture and value systems
Utian WH, et al. Menopause. 2002;9:402-10.
WHO Division of Mental Health. 1993.

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Alternative Approaches Used for


Vasomotor Symptoms

Lifestyle changes, cool environment

Vitamin E, dong quai, and black cohosh


no difference compared with placebo

Phytoestrogens

Clonidine (patch or pill)

Megestrol

SSRI/SNRI therapy

Gabapentin

SSRI/SNRI = selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor.

Life Style Modifications

CoreBodyTemperature
Exercise
BodyMassIndex
Smoking
RelaxationTechniques

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Post-Menopausal Treatment
Efficacy

Treats climacteric complaints


Prevents postmenopausal bone loss
Beneficial effects on cardiovascular parameters
Other benefits (cognitive function; reduction in
incidence of some cancers e.g. colon; etc..)

Safety

Endometrial cancer
Breast cancer

Lack of Adverse Effects

Non-Hormonal Treatment
Pharmacological

Antidepressants
Anticonvulsants
Antihypertensive
Vitamin E

Herbal-Nutritional

Black Cohosh
Phytoestrogens
Soy
Red Clover
Dong quai
Ginseng
Evening Primrose
Kava

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