Download Menopause - UNC School of Medicine

The Menopause
Anne Z. Steiner, MD, MPH
Assistant Professor
Reproductive Endocrinology and Infertility
University of North Carolina at Chapel Hill
Objectives
 Understand reproductive aging
 Physiology
 Stages
 Understand the physiologic changes and
symptoms associated with menopause
 Discuss treatment options for conditions
associated with menopause
 Define Premature Ovarian Failure
HRT= Hormone Replacement Therapy (EPT, ET)
ET= Estrogen alone
EPT= Estrogen plus Progestin
Reproductive Aging
 Decline in reproductive potential
 Puberty → Peak reproduction → Decline
in fertility → Anovulation (menstrual
irregularity) → Menopause
 Due to ovarian aging (physiology)
 Progresses with the decline in
oocyte/follicular pool
Reproductive Aging
Oocytes and Follicles
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Process begins in embryonic life.
20 weeks gestation - 6 - 7 million follicles.
At birth - 1.5-2 million follicles
At menarche - 300,000- 400,000 follicles
Follicular atresia continues throughout life.
Follicular loss accelerates when the total
number of follicles is ~25,000
 When follicles are sufficiently depleted
(<1000), menopause occurs.
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
Reproductive Aging
Hormonal Changes
Reproductive Aging
Hormonal Changes
Hypothalmus
GnRH
FSH
Estradiol / Inhibin B
+
Menopausal Ovary
Ovary
Stages of Reproductive
Aging
Reproductive Stage
Miscarriage Rate /
month
25%
12%
Pregnancy Rate /
month
20
30
37
40
Age in years
45
Stages of Reproductive
Aging
Perimenopause
 Follows period of declining fertility
 Precedes menopause
 Characterized by
 cycle irregularity (shortening then
lengthening)
 increasing symptoms
 Duration 2 to 8 years (average 5 years)
Diagnosing Perimenopause
 Clinical diagnosis based on
menstrual cycle pattern.
 Early follicular phase FSH and
symptoms may help solidify
diagnosis.
 Rule out hypothyroidism, depression
etc.
Perimenopause -- Symptoms:
Highly Variable

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
Vasomotor instability (85%)
Sleep disturbances
Mood disturbances.
Somatic symptoms:
 Fatigue, palpitations, headache, increased
migraine, breast pain and enlargement.
 Oligo-  Anovulation
 heavier or irregular cycles.
Managing Perimenopause
Goals:
 Patient education
 Prevention of endometrial cancer
 Individualized symptomatic relief
 Menstrual control
 Minimizing hot flashes
 Mood disturbances
Managing Perimenopause
Symptom
Relief
Menstrual Birth
Cycle
Control
Control
+++
+++
Endometrial
Cancer
Prevention
+++
Cyclic progestin +/therapy
+/-
-
++
Progesterone
IUD
-
+/-
+++
+++
EPT
++
-
-
+++
Hormonal
contraceptives
(oral or ring)
+++
Menopause
“The ovaries, after long years of service,
have not the ability of retiring in graceful
old age, but become irritated, transmit their
irritation to the abdominal ganglia, which in
turn transmit the irritation to the brain,
producing disturbances in the cerebral
tissue exhibiting themselves in extreme
nervousness or in an outburst of actual
insanity.”
AM Farnham, Uterine Disease as a factor in the production of
insanity. Alienist Neurologica 1887.
Menopause
 Marks the end of reproductive life
 Cessation of menses for 12 months
 Clinical diagnosis (not labs)
 Result of egg depletion and estrogen
production by the ovary due to….
 Natural aging or surgery
Menopause Facts
 Average age at menopause: 51 years
 (1% at age 40, 5% after age 55)
 Factors impacting age at menopause
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Maternal age at menopause
Tobacco use
SES/ Education
Alcohol use
Body Mass Index
 Factors that probably don’t impact on age at
menopause

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OCP use
Parity
Race
Height
Menopause
100
Age (years)
90
80
70
60
50
40
Age at menopause
30
20
10
0
1850
1940
2000
Date
*Projected estimate.
Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at:
http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02.
US Department of Health and Human Services. Healthy People 2010. Washington, DC: January
Summary of Key Physical Changes
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Vasomotor instability
Metabolic Changes
Coronary Artery Disease
Accelerated bone loss
Skin changes
Urogenital atrophy
Cognition (?)
Libido (?)
Brain
Eyes
Teeth
Vasomotor
Heart
Breast
Colon
Urogenital
tract
Skin
Bone
Hot Flushes (aka Hot Flashes)
 “Sudden onset of reddening of the skin over the
head, neck, and chest accompanied by a feeling of
intense body heat and sometimes concluded by
profuse perspiration”
 Number 1 complaint to physicians
 Few seconds to several minutes
 Rare to recurrent every few minutes
 Most severe at night and during times of stress
 More common among overweight women
 Usually last for 1-2 years
 25% will last for more than 5 years
Managing Hot
Flushes/Flashes
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Set realistic goals!
Lower the ambient temperature
Estrogen (80-95% reduction)
Alternative therapies

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High dose progestins
Tibolone
SSRI’s (Paroxetine, Fluoxetine(+/-))
SNRI (Velafaxine (+/-))
Gabapentin
Clonidine (+/-)
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.
11
12
Complementary Approaches
 May be effective
 Black Cohosh
 Soy/Phytoestrogens
 Vitamin E (1 hot flash per day less)
 No evidence
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Dong quai
Acupuncture
Yoga
Chinese herbs
Evening primrose
Ginseng
Kava
Red Clover Abstract
Sleep and Mood Disturbances
 Vasomotor episodes have an adverse impact
on quality of sleep
 Sleep disturbances lead to a reduced ability to
hand problems and stresses
 Women with a history of depression are at risk
of reoccurrence during menopause
 HRT may provide additional benefit to antidepressants in the management of
postmenopausal depression
Cognition
 Lack of agreement on impact of
menopause on cognition
 No clear evidence that HRT prevents
cognitive aging or enhances cognitive
function
 Vascular infarcts associated with
estrogen may worsen dementia in
women over 65
Metabolic Changes with
Menopause
Mechanisms of MenopauseRelated Increases in Adiposity
Preferential
abdominal fat
accumulation
Hormonal
changes of the
menopause
transition
Altered
energy
metabolism
Increased fat
accumulation
Increased
abdominal and
intra-abdominal
adiposity
“The Menopausal Metabolic Syndrome”

Lipid Triad
– Hypertriglyceridemia
–  LDL Cholesterol

  HDL Cholesterol
Abnormalities in Insulin
– Insulin resistance
  insulin secretion
–  insulin elimination
 Hyperinsulinemia
– HT reduces onset of DM and improves insulin resistance

Other Factors
– Endothelial dysfunction
–  visceral fat
–  uric acid
  SHBG
  blood pressure
  PAI-1
Cardiovascular Disease
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
Hormone Replacement Therapy
and CAHD
 Secondary Prevention of CAHD
 HERS (Heart and Estrogen/progestin
Replacement Study)
 No Benefit
 Primary Prevention of CAHD
 WHI (Women’s Health Initiative)
 No Benefit*********
*******Potential benefit to women 50-59 and/or within
2-3 years of the onset of menopause
Osteoporosis
Pathogenesis of Estrogen
Deficiency and Bone Loss
 Estrogen loss triggers increases
in IL-1, IL-6, and TNF.
 Increased cytokines lead to increased
osteoclast development and lifespan.
 Increased turnover of osteoblasts.
 Impacts vitamin D metabolism
 Impacts on renal and intestinal handling
of calcium
Consequences of Osteoporosis
 Spinal (vertebral)
compression fractures
 Back pain
 Loss of height and
mobility
 Postural deformities
 Colles’ (forearm)
fractures
 Hip Fractures
 Tooth loss
When to Measure BMD in
Postmenopausal Women
One or more risk factors
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Age > 65
Caucasian race
Family history
History of fracture
History of falls
Bad eyesight
Dementia
Early menopause
(<45)
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Smoking cigarettes
Low body weight
ETOH
Immobility*
Poor nutrition
Medications
Certain medical
conditions
Prevention of Osteoporosis
 Calcium
 1500mg elemental Calcium daily
 One serving of dairy=300mg
 Supplements (citrate, carbonate)
 Divided doses
 With meals
 Vitamin D supplementation
 Sunshine
 400 IU/daily
 Weight bearing exercise
 Smoking cessation
 Moderation of alcohol intake
Pharmacologic
(generally not recommended)
•HRT
•Raloxifene
•Bisphosphonates
Treatment of Osteoporosis
(for prevention of fractures)
 First Line Agents
 Bisphosphonates
 Raloxifene
 Second Line Agents
 Human recombinant PTH
 Nasal salmon calcitonin
 HRT
 Fall prevention strategies
Changes in the
Urogenital
System
Physiologic Changes in
the Urogenital System
 Decrease in production of vaginal
lubricating fluid
 Loss of vaginal elasticity and thickness of
epithelium (vaginal atrophy)
 Development of uretheral caruncles
 Mucosal thinning of urethra and bladder
Vaginal Atrophy
Urogenital symptoms
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Dysuria
Urgency
Frequency
Recurrent UTIs
Dysparunia
Pruritus
Stenosis
Treatment
1) Vaginal estrogen
(progestogen not
necessary)
2) HRT *
Hormone Replacement Therapy
Benefits
 Decrease hot flashes
 Prevents/treats osteoporosis and hip and
vertebral fractures
 Prevents/treats urogenital atrophy
Hormone Replacement Therapy
Risks
 Increased risk for venous thrombosis
and embolism**
 Increased risk for breast cancer with
prolonged (>3-5yrs) use (EPT, not ET)
 Increased risk for endometrial cancer
with ET (not EPT) (if uterus present)
**may be dependent on route of administration
Hormone Replacement Therapy
Areas of Concern
 Possible increase in cardiac events in
older women started on EPT (not ET)
 Probably increase in (ischemic) strokes
in older women started on HRT
Hormone Replacement Therapy
Areas of Concern
 Risks are dependent on
 Age (total mortality reduced by 30% if started at age
<60)
 Time since menopause
 Age at menopause
 Duration of therapy
 Type of HT
 Route of administration
 Dose of HT
 Benefits are dependent on
 Number of menopause related symptoms
Hormone Therapy
Guidelines
 Indication: estrogen deficiency symptoms
 Vasomotor symptoms
 Hot flushes, night sweats
 Disturbed sleep patterns
 Fatigue, concentration, memory
 GU atrophy
 Bladder irritability, vaginal dryness, dyspareunia
 Guiding principle
 Minimum dose for shortest time required
 Consider non-hormonal alternatives
Summary of Key Points
 Reproductive aging is due to a decline
in the number of ovarian follicles.
 Menopause


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
Signals the end of the reproductive years
Diagnosed clinically
Not a disease
Symptoms are due to estrogen deficiency.
Key Points
 CAD
 Rise in risk probably due to metabolic changes
 HRT not indicated for prevention or treatment at this
time
 Osteoporosis
 Evaluate all postmenopausal women over 65
(earlier screening recommended if they have one or
more risk factors)
 Prevention: Calcium, Vitamin D, weight-bearing
exercise, smoking cessation
 Primary treatment: Raloxifene, Bisphosphonates
Key Points
 Currently, the primary reason to prescribe
HRT in postmenopausal women is for the
relief of symptoms associated with
estrogen deficiency.
Premature Menopause
 Definitions:
 Early: age 40-44
 Premature: <40
 Causes
 Surgical removal of uterus**
 Surgical removal of ovaries
 Premature ovarian failure
**Further discussions exclude this group
Premature Ovarian Failure
 Sex chromosome abnormalities (usually
involving the X Chromosome)
 Fragile X premutation
 Autoimmune
 Chemotherapy/Irradiation
Evaluation of Premature
Ovarian Failure
 Karyotype (<30 years of age)
 Assessment for Fragile X premutation
(number of CGG repeats)
 Survey for other autoimmune diseases
(such as hypothyroidism, adrenal
insufficiency)
Premature Ovarian Failure
is Different from
Menopause !!!!
 10-20% of women with POF with normal
karyotypes will ovulate again
 5% spontaneous pregnancy rate
 Not normal reproductive aging
Treatment of Premature
Menopause
 Hormone replacement therapy!!!
 Counseling
 Oocyte donation
HIV and Menopause
 Mean age of menopause in HIV-infected women is 4748 (not adjusted for risk factors).
 May be difficult to differentiate HIV symptoms from
symptoms of menopause.
 Further research needed on the additive effects of
menopause, HIV, and anti-retroviral therapies.
 Further research need on depression during the
menopause transition in HIV affected women.
 Safety of HRT in HIV+ postmenopausal women has not
been studied.
Conde et al. Menopause 2009;16:199-213