Transcript Menopause Seminar 1

Management of Menopause
Zohreh Moosavi, MD
Mashad University of Medical Sciences
Educational Objectives
• Understand hormonal and physical changes
that occur with menopause
• Understand risks and benefits associated with
postmenopausal hormone therapy
• Learn about alternative therapies for
treatment of menopausal symptoms
What is Menopause?
• 12 months of amenorrhea (no menses)
• Average age 51
• Derived from the Greek words “men” (month) and
“pausis” (cessation)
• Primary ovarian function stops
• Marks the permanent end of fertility
MENOPAUSE
„Menopause is a physiologic process,
however, the consequences of ovarian
failure can diminish a woman’s quality of
life and can predispose her to osteoporosis
and increased risk of cardiovascular
disease.”
• Average age at menopause: 51 years
– 1% at age 40, 5% after age 55
Perimenopause
• Transition
• Change from normal ovulatory cycles to complete
cessation of menses
• Marked by menstrual irregularity
• May begin years( 5-10 years) prior to menopause
• Onset of menopausal symptoms
Perimenopausal Bleeding
• Anovulatory cycles can lead to hyperplasia
• Prolonged, heavy or frequent bleeding should raise
red flag
• Options for controlling bleeding (and protecting
endometrium against hyperplasia)
– Low dose birth control pills
– Cyclic progesterone
Menopause
• Marks the end of reproductive life
• Cessation of menses for 12 months
• Clinical diagnosis (not labs)
Changes in Hormone Patterns
• Inhibin levels fall
– Produced by granulosa cells
– Decrease may be from declining number of follicles or
reduced quality/capacity of aging follicles Speroff
• Serum FSH levels rise
• Slight increase in estradiol levels
Reproductive Aging
Hormonal Changes
Hypothalmus
GnRH
FSH
Inhibin B
+
Normal Ovary
Ovary
Reproductive Aging
Hormonal Changes
Hypothalmus
GnRH
FSH
Estradiol / Inhibin B
+
Aging Ovary
Ovary
Stages of Reproductive Aging
Reproductive Aging
Hormonal Changes
Hypothalmus
GnRH
FSH
Estradiol / Inhibin B
+
Menopausal Ovary
Ovary
PHYSIOLOGY OF MENSTRUATION AND
MENOPAUSE
Relative changes in FSH
as a Function of Life Stages
Life Stages
Chidhood
FSH (mIU/mL)
<4
Reproductive years
6 – 10
Perimenopause
14 – 24
Menopause
> 30
Healthy women over age 45 years
●We make the diagnosis of the menopausal transition or
“perimenopause” based upon a change in
intermenstrual interval with or without menopausal
symptoms (hot flashes, sleep disturbance, depression,
vaginal dryness or sexual dysfunction)
• A high serum follicle-stimulating hormone (FSH)
concentration is not required to make the diagnosis.
Ages 40-45 years
• ●Pregnancy – Serum hCG
• ●Hyperprolactinemia – Serum prolactin
• ●Hyperthyroidism – Serum TSH
For women under age 40 years
• Women in this age group with a change in
intermenstrual interval and menopausal
symptoms should not be diagnosed with
either the menopausal transition or
menopause. They have primary ovarian
insufficiency (premature ovarian failure). The
biology and natural history are different
MENOPAUSE
CATEGORIES OF SYMPTOMS:
1. Vasomotor disturbances:
hot flushes, night sweats, palpitations
headaches, muscle aches
2. Organ atrophy:
- vaginal dryness, atrophy, dyspareunia
- urinary incontinence, dysuria, infections
- breast atrophy
- skin dryness and thinning, brittle nails
Vasomotor Symptoms
• Most often begin in perimenopause
• Sudden onset reddening of the skin
(head/neck/chest), feeling of intense
body heat, profuse perspiration Speroff
• Intervals vary (minutes to hours)
• More frequent and severe at night
• Generally stop spontaneously
w/in few years, may persist
for many years
– 12-15 % of women in 60’s
– 9% of women after age 70 Casper
Other Causes to Consider
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Thyroid disorders
Pheochromocytoma
Leukemia
Cancer
Infection
Annual Incidence of Myocardial Infarction in
Women and Men in the U.S.
500
No.
X 103
400
Men
Women
300
200
100
0
29-44
45-64
Age, years
>65
Consequences of Osteoporosis
• Spinal (vertebral)
compression fractures
– Back pain
– Loss of height and
mobility
– Postural deformities
• Colles’ (forearm)
fractures
• Hip Fractures
• Tooth loss
Effect of ERT and HRT on Number
of Hot Flushes Over 12 Weeks
Adjusted Daily Mean
Number*
12
Placebo
0.625 CEE
0.625 CEE/2.5 MPA
10
8
6
4
2
0
1
2
3
4
5
6
7
8
9
10
Week
Efficacy-evaluable population included women who recorded taking study medication and had at least 7
moderate-to-severe flushes/day or at least 50 flushes per week at baseline.
*Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8).
Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79.
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A Bit of History:
• Estrogen initially prescribed as treatment for
vasomotor symptoms in 1960’s
• Use declined in mid 1970’s secondary to link to
endometrial cancer
• Use increased again in 1980’s when addition of
progestin determined to be protective
• Indications expanded to include prevention of
diseases of aging
Shifren JL, Schiff I. Role of Hormone Therapy in the Management of Menopause. Obstetrics
and Gynecology; 2010: 115, 4: 839-855.
Nurse’s Health Study
• Observational study
• > 70,000 initially healthy postmenopausal women
• Decrease in coronary events in women undergoing
hormone therapy
• Women aged 35-55 at baseline
Estrogen Benefits
• Oral estrogen lowers:
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LDL
Lipoprotein(a)
Glucose
Insulin
Homocysteine levels
Oxidation of LDL
• Increases
– HDL
Hormone Therapy - WHI
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Organized by NIH in 1992
Set of clinical trials
Primarily a trial of primary prevention of CV disease
Randomized, double blind, placebo controlled
27,347 postmenopausal women
40 US clinical centers
Hormone Therapy - WHI
• Combined estrogen-progestin arm
– 0.625mg conjugated estrogens and 2.5mg
medroxyprogesterone
– Randomized 16,608 women into either tx or placebo
– May 2002, Data and Safety Monitoring Board
recommended discontinuation of this arm
• Statistically significant increase in breast cancer
• Increase in CV events (CHD, stroke, venous TE)
Hormone Therapy - WHI
• Estrogen only arm
– 0.625 mg conjugated estrogens
– Randomized 10,739 women (s/p hyst)
– Feb 2004, NIH canceled study
• Increased risk of stroke similar to combined arm
• No increase or decrease in CHD
• Trend towards increased risk of probable dementia and/or mild
cognitive impairment
• Reduction in hip fractures
• No increase in breast cancer
Hormone Therapy - WHI
– WHI – largest and longest trial of postmenopausal
women using hormone therapy (5-7 years)
– Based on previous observational studies,
prevention of chronic conditions of aging in
women, including heart disease, was expected to
be demonstrated
– Instead found that hormones were associated
with a greater risk of CHD
Problems with WHI
• Mean age 63
• Fewer patients in the estrogen only arm (decreased statistical
power)
• Women with significant menopausal symptoms were
excluded (to limit drop out rate) – led to fewer women close
to their age at menopause
• Diagnostic bias possibility?
– 40.5 percent of estrogen-progesterone group, 6.8 of placebo group,
unblinded secondary to vaginal bleeding
– Unblinding not a problem in estrogen only arm Speroff
HERS Trial
• Heart and Estrogen/Progestin Replacement Study
• Secondary Prevention of CV disease
• 2763 postmenopausal women with established CHD were
randomized to placebo or continuous E/P
• Mean baseline age 67
• No reduction in the risk of CHD events
Ongoing Studies –KEEPS
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Kronos Early Estrogen Prevention Study
Women aged 42 to 58 years
At least 6 months, no more than 36 months postmenopausal
Randomized to oral CEE 0.45, transdermal 17B-estradiol 0.05
mg, or placebo (Micronized progesterone given orally 12
days/month).
• Primary prevention trial looking at intermediate markers of
CHD
– Intima-media thickness of the carotid artery
– Accruel of coronary artery calcium (Cardiac CT)
• Variety of risk factors including lipids, inflammatory factors,
coagulation indicators
Ongoing Studies – ELITE
• Early versus Late Intervention Trial with Estradiol
• 643 postmenopausal women
– randomized according to years since menopause (<6 or >10)
– To receive either 1 mg oral estradiol or placebo in double blind fashion
• Ultrasonography used to measure the rate of change in
thickness of the carotid artery
• Cardiac CT to measure coronary artery calcium
What Now?
• For women with moderate to severe vasomotor
symptoms, depending on individual risk, and
patient’s willingness to accept risk, use the lowest
dose of estrogen (with progesterone, if uterus intact)
effective for the shortest amount of time possible.
What dose ?
Estrogen Equivalents
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0.625 mg of conjugated estrogens
1 mg of micronized estradiol
0.05 mg of transdermal estradiol
5 mcg of ethinyl estradiol
How Long?
• Risk of Breast Cancer:
– For estrogen/progesterone therapy, time is limited by the
increased risk of breast cancer that is seen with more than
3-5 years of use
– For estrogen only, no sign of an increased risk of breast
cancer was seen during an average of 7 years of treatment
• Risk of Heart Disease/Stroke:
– Most healthy women below age 60 will not have an
increased risk of heart disease with hormone therapy
– In women below age 60, risks of stroke and blood clots are
less than 1/1000 women per year.
Cessation of Hormone Therapy
• Abrupt withdrawal increases return of moderate to
severe symptoms
• Tapering dose of hormones lowers risk of recurrent
symptoms
• Weaning off
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Decrease to lowest dose first
Decrease by one pill per week, or
Skip 1 day, then 2 days, etc
Slower tapering may benefit women with recurrence
Alternative Therapies
• Lifestyle modifications
– Keeping core temperature cool
– Regular exercise, weight loss
– Relaxation therapy/stress management
• Isoflavone supplements:
– Soy, red clover, black cohosh
Alternatives: SSRIs
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Venlafaxine
Fluoxetine
Sertraline
Citalopram
Paroxetine
Alternatives: Gabapentin
• Gabapentin reduces frequency of hot flashes
• Large study 420 women with breast cancer – 3
groups, randomly assigned, 8 wks
– Placebo – decrease 15% (hot flash score)
– 300 mg/d – decrease 31%
– 900 mg/d – decrease 46% Rapkin
• Other studies have shown similar results
Serum Hormone Levels
• Don’t check
• Evidence-based guidelines recommend
individualization of hormone therapy based on
symptoms, not hormone levels
– Lowest effective dose for shortest time possible!
Changes in the Urogenital
System
Most Common Complaints
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Vaginal dryness
Pruritis (itching)
Discharge – yellow, malodorous
Dyspareunia (painful intercourse)
Vaginal bleeding or spotting
Unlike hot flushes, symptoms do not improve with
time
Vaginal Atrophy
• Urogenital problems
– Urgency
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Dysuria
Abacterial urethritis
Recurrent UTIs
Urethral caruncles
Vaginal Atrophy – Treatment
• Regular sexual activity
• Water-based lubricants
• Low dose vaginal estrogen
Minidose of conjugated estrogen cream
Vaginal Atrophy – Treatment
• Estrogen replacement
– Sytemic and local are effective
– Low vaginal doses usually do not reach serum levels
sufficient to create systemic side effects (endometrial
stimulation) Bachman
• Creams, rings, tablets similarly effective
Should you add a progestin?
Summary
• Menopause is defined as 12 months without periods
• Symptoms can start up to 10 years prior
• Best Candidates for hormone therapy are women who:
– Are in their 50’s or younger
– Had their last menstrual period within the last 3 years
– Have moderate to severe symptoms
• Use lowest effective doses of hormones, for shortest duration
possible
• Take individualized risk factors into consideration (high blood
pressure, diabetes, smoking, excess weight, personal or family
h/o blood clots)
Endocrine Society Statement
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Hot flush treatment
Urogenital system
Bone
Colon cancer
Breast cancer
Veno trombotic risk
Stroke
Endometrial cancer
Cognition
Quality of life