Menopause Update: From the Menopausal Transition to Healthy Aging

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Menopause Update From the Menopausal Transition
to Healthy Aging

• Nancy Fugate Woods, RN, PhD, FAAN
• University of Washington
• School of Nursing

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Purposes

• Review the historical development of research
  support for womens health with particular
  emphasis on menopause
• Identify breakthroughs in menopause research over
  the past twenty years
• Challenge researchers and clinicians regarding
  needs for future research efforts related to
  menopause and healthy aging

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Aging of the Baby Boomers extended our focus from
menopause to healthy aging as part of the first
NIH Womens Health Research Agenda (1991)
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In 1991 the first Womens Health Initiative study
sites were funded Launch of the tri-part study
clinical trial of hormone therapy, calcium and
Vitamin D, low fat/high fiber diet the
observational study and the community prevention
studies led by the CDC
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March 1993 first National Institutes of Health
working conference on Menopause Current
Knowledge and Recommen-dations for Research
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• 1999 2nd NIH Womens Health Research Agenda
• Included attention to diverse populations of women

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Agenda for Research on Womens Health for the
21st Century The Menopausal Process (1999)

• Clarify and define the various stages comprising
  the transition from premenopause to perimenopause
  to postmenopause
• Characterize the normal antecedents and sequellae
  of the menopause transition, distinguishing the
  influence of menopause from disease processes
  and the aging processes
• Behavioral aspects of menopause
• Pharmacologic issues related to menopause

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Breakthroughs in Menopause Research

• Staging the Menopausal Transition
• Characterizing Womens Physiology during the
  Menopausal Transition
• Identifying Symptoms associated with the
  Menopausal Transition and their Correlates
  Basis for Symptom Management
• Identifying the Consequences of Menopause for
  Healthy Aging

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Staging Reproductive Aging Workshop (STRAW)

• Workshop sponsored by the National Institute on
  Aging, National Institute of Child Health and
  Human Development, North American Menopause
  Society and American Society for Reproductive
  Medicine 2001
• Purposes
• Develop preliminary staging system for the
  menopause transition
• Re-evaluate existing nomenclature
• Identify knowledge gaps and future research
  opportunities

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Benefits of a Staging System

• Researchers and clinicians would be able to
  compare cases and compare data across studies
• Women would understand the timing and duration of
  the transition to menopause, the consequences for
  their fertility, and whether their bleeding
  patterns were normative
• Clinicians and women time could time decisions
  about assessment and prevention, e.g.
  osteoporosis screening (Mitchell, Woods
  Mariella, 2000)

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Proposed Staging System for the Menopausal
Transition (STRAW Conference Soules et al 2001)
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The Seattle Midlife Womens Health Study
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Study Design Seattle Midlife Womens Health
Study

• Longitudinal study with 508 women interviewed
  between 1990-1992
• Annual follow-up since enrollment with 344 women
  starting longitudinal study in 1992
• Cohort included 220 participants in 1996 when
  monthly urine samples were added to study and and
  193 in 2000 when DNA samples were obtained
• Women had 16 years of education, 85-91 employed,
  75-89 white, and 68-69 partnered

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MENSTRUAL CYCLE CALENDAR Early Transition
(SWMHS-Mitchell et al 2000)Late Reproductive
(STRAW-Soules et al 2001)
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MENSTRUAL CYCLE CALENDAR Middle Transition
(SWMHS)Early Transition (STRAW)
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MENSTRUAL CYCLE CALENDARLate Transition
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Age of Onset and Duration of Menopausal
Transition Stages (Mitchell, Woods, and Mariella,
20002006 update)
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Study of Womens Health Across the Nation (SWAN)
began in September,1994 with funding from the
National Institute on Aging, and additional
support from the National Institute of Nursing
Research and the Office of Research on Womens
Health.
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Goals of SWAN

• To describe the chronology of the biological and
  psychosocial characteristics of the menopausal
  transition
• To describe the effects of this transition on
  subsequent health and risk factors for
  age-related chronic conditions
• Emphasis placed on
• Multi-ethnic samples
• Community or population-based sample

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Characterizing Womens Physiology during the
Menopausal Transition

• SWAN Study included Daily Hormone Study over
  multiple years as well as annual blood draws,
  interviews, clinical exams, and questionnaires
• Representation of multiple American ethnic groups
  of women African-, Chinese-, Japanese-,
  Hispanic and White-Americans
• Women ages 42-52 at entry to study, still being
  followed

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SWAN Cohort Composition
New Jersey
Pittsburgh
Michigan
UC Davis
Boston
Chicago
UCLA
162
199
281
250
248
286
325
934 281 250 286 1550
African Am
301
Japanese
253
208
215
209
Chinese
146
218
Hispanic
Caucasian
452 463 456 543 496 459 432 3301
Total
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Model for Ovarian Aging (Santoro 2005)
FMP
Stable Ovarian Function
Critical Level of Follicle Depletion
Subsequent Progress Multiple Modifying Factors
Santoro 2005
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Comparison of Reproductive Age and Perimenopausal
Womens Cycles
Santoro 1999
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Increased E2 as ovary overshoots response to FSH
Santoro 1999
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Mechanisms Initiating Menopause

• Does central nervous system aging or clocks
  control the onset of menopause, e.g. by altering
  sensitivity to ovarian steroids? Increasing the
  elaboration of FSH?
• Does ovarian aging control the onset of
  menopause, e.g. by follicular depletion?
  Producing less estrogen? Anovulatory cycles?

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Presence of Luteal Activity by Age SWAN
Data (Santoro 2003)
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Hypothalamic-pituitary Sensitivity to Estrogen
(Weiss et al 2005)

• SWAN Participants were studied in a daily urinary
  hormone study (n848)
• Three groups of women were studied who had
• estrogen increases and an LH surge
• estrogen increases without an LH surge
• neither estrogen increases nor an LH surge

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Decrease in Estrogen Sensitivity

• Anovulatory cycles with estrogen peaks were
  frequent in older reproductive age women in
  these women there is evidence of failure of the
  estrogen-positive feedback on LH secretion to
  trigger ovulation
• In anovulatory cycles follicular estrogen levels
  did not lower LH secretion as occurs in younger
  reproductive age women there is decreased
  estrogen-negative feedback on LH secretion
• (Weiss et al, 2005)

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Melbourne Midlife Womens Health Project

• Charted the course of the natural transition to
  menopause for a population based sample of
  Australian white women (N453) (begun 1990)
• Compared women who remained in the late
  reproductive stage or in the menopausal
  transition with those who became postmenopausal
  over an 8 year period

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Burger et al 2000
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DHEAS by FMP and Age (Burger 2000)
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The Seattle Midlife Womens Health Study
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FSH by Menopause Transition Stages Middle
Post Seattle Midlife Womens Health Study
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Estrone (E1G) by Menopause Transition Stages
Middle to Postmenopause
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Estrone and FSH Levels (Urinary) by Menopausal
Transition Stages Seattle Midlife Womens
Health Study
Di Julio et al, in press Maturitas
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Understanding Symptoms and their Correlates
Menopausal Transition

• National Institute on Aging proposed that the NIH
  office of Medical Applications of Research (OMAR)
  Consensus Development Program convene an NIH
  State of the Science Conference on Management of
  Menopause-Related Symptoms (March 2005)
• Proceedings published in special Issue of the
  American Journal of Medicine (vol 118, no 12B,
  2005)

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Which symptoms do women report during the
perimenopause?

• Vasomotor symptoms hot flashes and night sweats
• Dysphoric Mood e.g depressed mood, irritable,
  tense
• Sleep disruption
• Sexual concerns or problems
• Cognitive changes e. g. forgetful
• Vaginal dryness
• Urinary incontinence
• Somatic/bodily pain symptoms
• Breast pain
• Bleeding symptoms

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Seattle Midlife Womens Health Study

• Charting the course of the natural transition to
  menopause for a population based sample of 35-55
  year old white, Asian, and African American women
  (n375) in longitudinal study begun in 1990 and
  followed until 2006
• Women were in late reproductive stage or early
  menopausal transition stage at recruitment
• Women provide daily health diary recordings for 3
  days per month, monthly early am urine sample for
  endocrine analyses, and annual health update
• Symptoms rated from 0 (absent) to 4 (extreme)

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Do symptoms persist beyond the final menstrual
period?

• Difficult to answer owing to lack of data beyond
  the first year after the final menstrual period
  in most studies
• Prevalence estimates indicate persistence of
  symptoms in 40-50 of women
• Severity for hot flashes increases after the FMP

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FSH
HOT FLASHES
MT STAGE
BMI
Other correlates include Passive smoke, Lo
activity, Alcohol intake PMS history, Anxiety,
stress, lo income education, attitudes toward
menopause
SHBG
AGE
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Menopausal transition stages
FSH,LH, E2 variability,Depressed mood
BMI
Poor health, Hot flashes and sleep symptoms
Other correlates Smoking, lo activity, poor
health, other symptoms, family history, PP
blues, anemia
Stress
History of depression
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FSH, E2, DHEAS
Pdg
BMI
Menopausal transition stages
Sleep Symptoms
Anxiety, hot flashes
Other correlates SBP DBP WHR
Smoking, lo physical activity, caffeine
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Figure 1. Factors Influencing Sexual Desire
during the Menopausal Transition and Early
Postmenopause
Aging Age
/-
Sexual Desire interest in sexual expression
Menopausal Transition Factors MT stages, E1G, T,
FSH, HRT use
/-
Health-related factors Perceived health,
health-related behaviors (exercise, alcohol,
smoking)
/
-
/-

Symptoms Hot flashes, depressed mood, anxiety,
fatigue, vaginal dryness, disrupted sleep

Stress Perceived stress, sexual abuse history
Social opportunity factors Employment, education,
partnered, parenting
/-
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E1
E1
FSH
LOWER SEXUAL DESIRE

-
FSH T
HOT FLASHES
VAGINAL DRYNESS
NIGHT-TIME AWAKENING
DIFFICULTY CONCENTRATING
EARLY AWAKENING
T
FORGETFUL
Women experience clusters of symptoms Sleep is
associated with many
FSH
DEPRESSED MOOD
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Massachusetts Womens Health Study

• Charted the course of the natural transition to
  menopause for a population based sample of white
  women (N2352) (begun 1982)
• Symptoms studied with telephone interview
  repeated at 9 month intervals
• Tracked use of health services related to
  menstrual and menopausal symptoms

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Menopause and Healthy Aging A Lifespan View of
the Menopausal Transition
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Leading causes of US mortality National Center
for Health Statistics
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Healthy Aging and Menopause Findings from the
SWAN Study

• Bone
• Body composition
• Metabolic syndrome
• CVD
• Cognition
• Depression

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Bone Health SWAN Data

• Bone loss accelerates in the late menopausal
  transition
• 0.018 g/cm2/yr in spine
• 0.105 g/cm2/yr in hip
• Bone loss also continues in the early PM
• 0.022 g/cm2/yr in spine
• 0.013 g/cm2/yr in hip

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Bone Health

• FSH (not E2) predicts bone loss
• Bone loss is slower in heavier women
• Higher sport activity and higher home physical
  activity associated with higher spine and hip BMD
  (Finkelstein)
• African American, Chinese- and Japanese-American
  women had greater bone density than white women
  (Sowers 2003)

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Body Composition Changes SWAN Data

• Cumulative 6 year increase in fat mass of 3.4 Kg,
  continues to increase PM
• Cumulative 6 year decrease in skeletal muscle of
  0.23 Kg
• Cumulative waist circumference increase of 5.7
  cm, slows 1 year after FMP
• FSH associated with increased fat mass (Sowers et
  al, 2007)

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Metabolic Syndrome

• Abdominal Obesity (waist 35 in)
• Atherogenic displidemia
• Triglycerides 150md/dl
• LDL-C
• Small dense LDL
• Hypertension (BP 130/85 mm Hg)
• FBGlucose 110 mg/dl
• (ATP III)

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Metabolic Syndrome

• Insulin resistance /- glucose intolerance
• Prothrombotic state
• Proinflammatory state

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Lipoprotein Profile Across Menopausal Transition
Stages
(Carr et al 2002)
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Estradiol
-
Testosterone

METABOLIC SYNDROME
-
DHEAS
-
Influence of Endocrines on Metabolic Syndrome
(Santoro 2005 Sutton-Tyrell 2005)

SHBG
Free Androgen Index (FAI)
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Cardiovascular Disease Risk Factors

• Have we been focusing on the wrong hormones?
• As the testosterone estrogen ratio increases
  over the menopausal transition, there is an
  increase in the incidence of metabolic syndrome
  (Torrens, J et al, 2008)
• Androgens (FAI) and low SHBG were associated with
  elevated CV risk factors higher insulin,
  glucose, and hemostatic and inflammatory markers
  and adverse lipids estrogen had lesser effects
• During the MT, vasculature may be vulnerable

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Cardiovascular Disease Risk

• During the late MT and early PM the lumen size of
  the carotid artery becomes larger (Wildman et
  al, 2008)
• Adventitial diameters increase compared to late
  reproductive stage and early MT
• Do these factors indicate that vascular
  tone/physiology is changing? Or is this a
  vascular structural change? An acute or permanent
  change? Modify HT effects?

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Mechanism of Cardiovascular Disease Estrogens
and Progestins
Shufelt, Merz,,JACC, 200953(3)
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Cognition and Memory

• 1657 women, 49.7 years of age
• Battery of cognitive Tests administered over 4
  year period (verbal memory, working memory and
  processing speed
• No association between endocrine levels,
  menopausal transition stage and cognitive
  performance tests
• Longitudinal results indicate strong learning
  effects of the test with continued GAINS in
  performance (learning effect)

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• During late MT a small decrease in the rate of
  improvement in the SDMT
• This would be expected to occur with age
• Stay tuned for further SWAN data!

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Depression during the Menopausal Transition

• Women experience an increased incidence of
  depressed mood during the late MT vs earlier
  (Bromberger 2007)
• Consistent with the findings from the Seattle
  Midlife Womens Health Study (Woods et al, 2008)