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Transcript
Menopause
UNC School of Medicine
Obstetrics and Gynecology Clerkship
Case Based Seminar Series
Objectives for Menopause
 Define menopause and describe changes in the hypothalamicpituitary-ovarian axis associated with perimenopause and
menopause
 Recognize symptoms and physical exam findings related to
perimenopause and menopause
 Discuss management options for patients with perimenopausal
and menopausal symptoms
 Counsel patients regarding the menopausal transition
 Discuss long-term changes associated with menopause
Epidemiology
 Average age is 51.4 years
 95% confidence interval of Bell Curve gives a range of 45-55
years. Less than 2% occur before age 40.
 Factors associated with early menopause




Cigarette smoking (1.5 yrs earlier)
History of short intermenstrual interval
Family history
Chemo / Radiation / Genetic factors
 Unrelated to number of prior ovulations, pregnancies, use of
OCPs, height, weight, age at menarche, race, class or
education
Elderly Population
 In 2000, life expectancy
 Women 79.7 years
 Men
72.9 years
 Once you reach 65
 Women expect to live until 84.3 years old
 Men expect to live until 80.5 years old
 Therefore, more than 1/4 of a woman’s life is spent in
menopause
Peri-Menopause
 Peri-menopause
 Transitional period
 Hallmark is menstrual irregularities
 Shortened cycle length
 Skipped cycles
 10% of women will have abrupt cessation of menses
 Median length of 4-5 years
 Median age of onset is 47.5 years
Physiology
 Definition
 No menses for 12 consecutive months
 No other identifiable cause
 Depletion of follicles with loss of granulosa and thecal
cell function
 6-7 million oocytes at 20 weeks fetal age
 1 million oocytes at birth drop to 400,000 at puberty
 300-400 ovulatory events over lifetime
 Accelerated follicular loss 2-8 yrs before menopause
Physiology
 Depletion of follicles with loss of granulosa and thecal
cell function
 Granulosa cells produce less inhibin, which provides negative
feedback for FSH secretion by the pituitary gland
 Increase in FSH levels
 After menopause, LH levels are also elevated
 Would you check a FSH or LH level to diagnose menopause?
Symptoms
 Menstrual irregularities
 Primary reason women seek medical attention!
 Cycles shorten as increased FSH triggers early ovulation
 Skipped cycles due to anovulation
 Long periods of anovulation can lead to
 Excessive estrogen states
 Irregular, unexpected menses
Patient Counseling
• What can women expect?
– Discuss expected age of onset (51.5 years)
– Discuss possible symptoms to expect
– Discuss treatment options
Symptoms
 Do you think the perimenopausal women can get
pregnant?
 YES
 Guinness World Record = 57 yrs & 120 days
 So, remember to recommend contraception. Low-dose
oral contraceptives may be used in women without
contraindications (i.e. non-smokers).
Symptoms
 Hot Flushes
 Subjective feeling of intense heat followed by skin
flushing and diaphoresis.
 Sudden dilation of peripheral vasculature secondary to
abrupt estrogen withdrawal. Skin temperature increases
and core temperature drops.
 Usually, occurs for a few seconds to minutes.
 Duration is about 1-2 years. 25% for > 5 years.
Symptoms
 Genitourinary atrophy
 A variety of symptoms
 Atrophic vaginitis, urethritis, recurrent UTIs, dyspareunia
 Pelvic organ prolapse is NOT caused by estrogen
deficiency
Symptoms
 Urinary Incontinence
 Atrophy of estrogen-dependant tissues such as the
urethra may contribute to existing causes for urinary
incontinence
 Typically addressed with local application of estrogen
cream
Symptoms
 Sexual Disturbances
 Decreased interest in sexual activity
 May be related to decreased testosterone levels
 May be related to psychosocial stressors
 Anatomic changes secondary to estrogen deficiency
 Atrophy of vaginal mucosa and lower urethra
 Thinning of vaginal mucosa with decreased lubrication and
elasticity, leading to dyspareunia
Symptoms
 Sleep Disturbances
 Estrogen appears related to producing restful,
deep-stage sleep
 Hot flushes more common at night
 Wakening or disruption of deep-stage sleep
 Contributes to feeling of overall fatigue
Symptoms
 Mood Swings / Irritability / Depression
 NOT associated with menopausal hormone changes
alone
 Stage of life associated with multiple changes (e.g.,
children leaving home, parents aging, retirement)
 Hot flushes and fatigue can lead to emotional lability
Symptoms
 Cognitive Function
 Some types of memory and brain function may be
influenced by estrogen
 Some evidence suggests that Alzheimer’s disease is less
frequent in estrogen users and the effect was greater
with increasing dose and duration of use.
Adverse Health Effects
 Cardiovascular Disease
 Leading cause of death in US women (Ahead of cancer,
cerebrovascular disease and MVAs)
 Death rate for CV disease is 3X the rate for breast cancer
and lung cancer.
 Changes in lipid profile in menopause
 Increased LDL
 Decreased HDL
 ? Decrease in triglycerides
Adverse Health Effects
 Osteoporosis
 Spinal bone density peaks at 20 years, while cortical bone
density peaks in late 20s
 Rate of loss of 0.5%/year prior to age 40, then anywhere
from 2-9%/year for first 10-15 years after menopause
 Primary loss is trabecular bone, leading to compression
fractures, loss of height, kyphosis
Adverse Health Effects
 Osteoporosis
 Osteopenia = BMD between -1 and -2.5 SD of a young, white
adult woman.
 Osteoporosis = BMD -2.5 or greater SD
 25-50% of women will have spinal compression fractures by
age 70
 20% of Caucasian women age 80 will have hip fractures, with
15-20% mortality.
 Annual incidence is 1.3% after age 65
Adverse Health Effects
 Osteoporosis
 High risk:
 Caucasian, Asian
 Thin, inactive, smokers
 High caffeine/alcohol intake, low dietary calcium, high
dietary protein and phosphates
 H/o oligomenorrhea, excessive exercise, eating disorder
 Medical conditions – hyperthyroid, cancer,
myeloproliferative disorders
 Low Risk:
 African American
 Obese, active
Adverse Health Effects
 Osteoporosis
 Protection:
 Ca supplements (1200mg, 1500mg)
 Weight-bearing exercise
 HRT: estrogen increases
 Intestinal calcium absorption
 Renal conservation of calcium
 Increases 1,25-dihydroxyvitamin D (active form)
 Vitamin D (400-800IU)
Hormone Replacement
 Types of hormone replacement
 Estrogen alone (for women without a uterus)
 Estrogen and progesterone
 Sequential
 Continuous
 Local estrogen
 SERM’s (Selective Estrogen Receptor Modulators)
HRT: Advantages
Relief of vasomotor symptoms
 HRT is effective in reduces the number of hot flashes
 6-8 weeks to see maximal effect
 Combination HRT (0.625mg estrogen/2.5mg MPA)
 What about lower doses of HRT?
 For combination HRT, all doses resulted in similar relief of
symptoms
 For estrogen alone, most relief with higher doses
HRT: Advantages
Vaginal atrophy
 Menopause thins the vaginal epithelium and increases
the vaginal pH (> 6.0).
 Estrogen decreases the vaginal pH, thickens the vaginal
epithelium and reverses vaginal atrophy.
 Less atrophic changes with higher doses of HRT
HRT: Advantages
Bone protection
 Reduction of bone loss
 Prevents OP-related hip fractures
 Protects the spine and the small bones
 WHI: 5 fewer hip fractures per 10,000 person-yrs
HRT: Advantages
Colon cancer
 Some observational studies have suggested a reduced
risk.
 WHI: 6 fewer cases / 10,000 person-yrs
HRT: Disadvantages
Endometrial cancer
 8-10 fold increased risk with unopposed estrogen.
 PEPI: unopposed estrogen x 3 yrs = 24% with atypical
hyperplasia (vs 1% women on placebo)
 Risk is increased with:
 Increased duration and dose
 Continuous versus cyclic therapy
 Absence of a progestin
HRT: Disadvantages
Breast cancer
 Meta-analysis of 51 case-controlled & cohort studies
showed no increased risk with short-term use.
 After 5 years of use, risk increased by 35%.
 WHI: 8 more invasive cases / 10,000 person-yrs
 Women diagnosed with breast cancer while using HRT
have been shown to have better survival
HRT: Disadvantages
Thromboembolic disease
 Increases risk for DVT 2 – 3.5 fold
 Strokes: 8 more / 10,000 person-yrs
 PEs: 8 more / 10,000 person-yrs
HRT: Disadvantages
Cardiovascular disease
 Traditionally, HRT was thought to provide protection
against coronary heart disease (CHD)
 Observational studies found lower rates of CHD in
postmenopausal women on HRT.
 The consensus was that CHD was about 35-50% lower in
women using HRT.
 Many studies showed that HRT improved lipid profiles.
HRT: Disadvantages
Cardiovascular disease
 What about secondary prevention? i.e. women who
have a h/o coronary heart disease, does HRT help?
 Heart and Estrogen/Progestin Replacement Study
(HERS) was a RCT, double-blinded study of 2,763 PM
women with intact uteri and a h/o CHD
 52% higher rate of major coronary events in the 1st year
 Then there was a reduction in the risk with longer use –
i.e. 33% lower risk in the 4th and 5th years
HRT: Disadvantages
Cardiovascular disease
 What about primary prevention? i.e. in healthy women,
does HRT prevent CHD?
 Women’s Health Initiative (WHI)
 RCT of 16,608 postmenopausal women aged 50-79
years old with an intact uterus
 40 different US centers
 Combination HRT – 0.625mg CEE and MPA 2.5mg vs
placebo
HRT: Disadvantages
Cardiovascular disease (WHI)




7 more CHD events
8 more strokes
8 more PEs
8 more invasive cancers
 Study stopped after 5.2 yrs (planned 8.5yrs) because of
cases of breast cancer
Hormone Alternatives
 SERMs
 Selective estrogen receptor modulators
 Work as agonists and antagonists depending on the tissue
 Raloxifene and tamoxifen
SERMs
Estrogen
Raloxifene
Tamoxifen
Prevent OP
↑↑↑
↑↑
↑
Risk Breast
Cancer
↑↑
↓↓
↓↓
Hot Flashes
↓↓↓
↑
↑
Endometrial
Cancer
↑↑
no effect
↑
Venous
Thrombosis
↑↑
↑↑
↑↑
Hormone Alternatives
 SERMs
 Overall, SERMs can help to prevent OP and breast cancer
 However, they aggravate hot flashes, the most common indication for
estrogen therapy
 Tamoxifen stimulates the endometrium
Alternative Medicine
 Limited studies with relatively short duration of therapy and
follow-up.
 Soy and isoflavones may be helpful in the short-term (< 2
yrs) for vasomotor sx and may protect against osteoporosis.
 Large amounts needed: 35-75mg qd isoflavones/day
 Black cohosh may be helpful in the short-term (< 6 mos) for
vasomotor symptoms.
Summary: Hormone Replacement
Benefits
Detriments

Vasomotor sx

Endometrial ca

Vaginal atrophy

Breast ca

Osteoporosis

VTE

Colon cancer

CHD
Bottom Line Concepts
 Menopause is the natural course aging of the female reproductive
system, driven by loss of oocytes
 Symptoms of menopause include








Menstrual irregularities
Hot flushes
Sleep disturbances
Mood changes
Sexual disturbances
Urinary incontinence
Cognitive function
Hair growth
 Health risks of menopause include osteoporosis, lipid abnormalities,
cardiovascular disease, and cancer.
 Treatment options include HRT, SERMs, soy, isoflavones, black cohosh
 Risks/benefits of HRT and SERMs need to be discussed
Case: Abnormal Bleeding
 A 44-year old woman presents for evaluation of abnormal menstrual
bleeding. Her periods have been regular in the past but for the last 6
months she has had a period every 35-56 days, lasting 7-9 days. The
bleeding is heavier than usual and she feels tired all the time. She has
gained 15 lbs over the last 2 years, which she believes is due to lack of
exercise and increased eating/sleeping. She complains that her skin is dry.
Exam is unremarkable. What would your recommend next?





Check pregnancy test
Discuss exercise / eating patterns
Check TSH, PRL
Consider endometrial biopsy
Expectant management versus hormonal management
Case: Health Maintenance
 58 year old postmenopausal woman referred to you by a friend. She has
no known medical problems and is on no medications. Her social history is
remarkable for an 80-pack/year history of tobacco use. Her physical exam
is unremarkable. What are the important health maintenance aspects of
the exam to focus on?







Blood pressure
Pelvic exam
Breast exam / mammography
Fecal occult blood
Smoking cessation
Flu shot
Osteoporosis
Case: Abnormal Bleeding
 A 47 year old woman, G2P2, presents with menstrual cycles varying in
length from 20 to 40 days. Until 9 months ago she had regular 28 day
cycles. She reports frequent hot flushes. She recently resumed sexual
activity and uses no contraception, but she does not desire pregnancy. She
does not smoke and has no other medical problems. Her physical exam is
unremarkable. What are her options for cycle control?





Low dose combination oral contraceptive
Continuous low dose estrogen and progestin menopause regimen
Cyclic progestin therapy for 12 days a month
Continuous low dose estrogen (0.625mg conj EE)
Estradiol vaginal ring
Case: Osteoporosis
 A menopausal patient with osteoporosis has been reading information on
the Internet about different treatment modalities for osteoporosis. She
wishes to know more about what therapies are actually available and how
they work?
 Estrogen: Reduces osteoclast activity
 SERMs: Reduces osteoclast activity
 Bisphosphonates: Reduces osteoclast activity
 Take on empty stomach, first thing in AM with 8oz water and no food for 30
minutes
 Take sitting up due to esophagitis risk
 Calcium supplementation within 4 hours
 Calcium / Vitamin D supplements
References and Resources
 APGO Medical Student Educational Objectives, 9th edition, (2009),
Educational Topic 47 (p100-101).
 Beckman & Ling: Obstetrics and Gynecology, 6th edition, (2010),
Charles RB Beckmann, Frank W Ling, Barabara M Barzansky, William
NP Herbert, Douglas W Laube, Roger P Smith. Chapter 37 (p329-336).
 Hacker & Moore: Hacker and Moore's Essentials of Obstetrics and
Gynecology, 5th edition (2009), Neville F Hacker, Joseph C Gambone,
Calvin J Hobel. Chapter 35 (p379-385).