Lecture at 2010 annual convention of Philippine Society of Climacteric Medicine

1. Perimenopause &
Metabolic Syndrome:
Is there a link and what
should be done about it?
Iris Thiele Isip Tan MD, FPCP, FPSEM
MS Health Informatics (cand.)
Clinical Associate Professor, UP College of Medicine
Section of Endocrinology, Diabetes & Metabolism
Department of Medicine, UP-Philippine General Hospital

2. High
triglycerides
Hypertension
Low HDL-C
Obesity
Glucose
intolerance
Metabolic Syndrome

3. Cross-sectional data
MetSyn increases
from premenopause
to postmenopause,
independent of age.

4. Low
HDL-C
Hypertension
(Peri)
Menopause
High
triglycerides
Glucose
intolerance
Obesity

5. 2406 J Clin Endocrinol Metab, June 2003, 88(6):2404 –2411
risk
diabetes
hypertriglyceridemia
small dense LDL
hypertension
CVD Estrogen
promotes
gluteo-femoral
fat distribution
Carr M et al JCEM 2003;88:2404-11
FIG. 1. Patterns of body fat distribution.

6. e the major determinant of the metabolic
Changes in LDL with menopause
high amounts of visceral fat have an excess
ar mortality and associated metabolic abnor- Postmenopausal women have higher to
Menopausal fat redistribution ➨ MetSyn
When Pascot et al. (32) matched women for
by CT scan) and menopausal status, the dif-
LDL cholesterol, triglycerides (TG), and
[Lp(a)] levels and lower HDL cholesterol l
y found in very low density lipoprotein menopausal women (38 – 40). Although elev
DL, large buoyant HDL2 particles, LDL par- a component of the metabolic syndrome, LDL
glucose, C peptide, and blood pressure were by 10 –20% (23, 41) with menopause, and the
action of genetic and environmental factors influences the manifestation of the metabolic syndrome.
t (IAF) are associated with increased insulin resistance (IR) and FFA levels, and decreased adiponec
eased secretion of apo B-containing particles, leading to hypertriglyceridemia and increased HL activity
mall dense LDL particles and a reduction in the large antiatherogenic HDL2 particles.
Carr M et al JCEM 2003;88:2404-11

7. Sex- and menopause-associated
changes in body-fat distribution
DEXA measurement
Premenopausal women
Men Regular menses
21-79 y No menopausal sx
n = 103 19-51 y
n = 61
-
?:,
i .
Postmenopausal Good health ): . .
Amenorrhea Not obese
1.
Elevated LH & FSH (BMI 18.8-28) !
43-63 y No meds affecting
n = 70 lipid/bone metabolism .
-
.
Ley et al Am J Clin Nutr 1992;55:950-4

8. Increased android fat in menopause
2406 J Clin Endocrinol Metab, June 2003, 88(6):2404 –2411
*** p <0.001
60
eliminated, implying
menopausal status a
n = 103
Regional differences
***
n = 70 tivity in postmenop
50
changes in fat accum
n = 61 *** ing (33, 34). Adipone
% *** may play a role in the
are inversely related
40 ever, the only study
revealed no differen
(35).
Menopause is als
30 mass (muscle) and t
Pre- Post-
physical activity (36)
Males
menopausal menopausal
maximal oxygen con
menopausal (VO2 m
FIG. 1. Patterns of body fat distribution. Ley et al Am J Clin Nutr 1992;55:950-4
age-matched premen

9. Decreased gynoid fat in menopause
ab, June 2003, 88(6):2404 –2411 Carr • Menopause and the
eliminated, implying <0.001 differences in
*** p that the
60
menopausal status accounted for the metab
Regional differences in adipose tissue lipop
tivity in postmenopause may account for
n = 61
changes in fat accumulation, but results to
***
50
ing (33, 34).= 70
n Adiponectin, a novel adipocyte-
may play a*** in the metabolic syndrome, a
role
% are inversely related n = obesity and insulin
to 103
ever, the only study evaluating adiponecti
***
40 revealed no difference in pre- and postmen
(35).
Menopause is also associated with red
mass (muscle) and this appears to be rela
30 physical activity (36). Lynch et al. (37) recentl
Pre- Post-
maximal oxygen consumption (VO2 max) in
Males
menopausal menopausal
menopausal (VO2 max) women compared
erns of body fat distribution. age-matched premenopausal women and f
relationship betweenAm J Clin Nutr 1992;55:950-4
Ley et al
visceral adiposity and
gain, most studies do not reveal in-

10. Is androgen dominance in
menopause associated with
development of MetSyn?
Hallmark of
menopausal
transition is
dramatic reduction
in estradiol

11. SWAN Cohort & Metabolic Syndrome
Study of the Women’s Health Across the Nation
n = 949; 9-year follow-up
Premenopause or early Primary outcome:
perimenopause MetSyn (NCEP-ATP III)
Reached menopause Secondary outcome:
during the study MetSyn components
Never took hormone therapy
No diabetes or MetSyn at Serum T, SHBG and
baseline estradiol
Janssen I et al Arch Intern Med 2008;168(14):1568-75

12. Hormone Levels in SWAN Cohort
With and Without MetSyn
Hormone levels, Cohort without Cohort
Total Cohort
median (IQR) MetSyn with MetSyn
38.0 37.6 42.5*
Testosterone, ng/dL
(26.5-51.0) (25.8-50.4) (30.4-53.9)
3.13 2.89 4.52**
Bioavailable T, ng/dL
(1.78-5.32) (1.58-4.86) (2.48-7.08)
4.88 5.06 3.83*
SHBG, ug/mL
(3.37-6.80) (3.54-7.21) (2.52-5.46)
25.5 26.6 21.8**
Estradiol, pg/mL
(14.8-65.0) (14.7-69.5) (14.4-34.8)
* p<0.05 ** p<0.001
Janssen I et al Arch Intern Med 2008;168(14):1568-75

13. SWAN Cohort &
Metabolic Syndrome
*Adjusted for age, age at final menstrual period, ethnicity,
study site, baseline BMI, change in BMI from baseline,
baseline education level, marital status and smoking
New-onset MetSyn by
final menstrual period:
Odds of MetSyn increased by 13.7%
10% for every 1-SD increase
in bioavailable T levels* Odds of MetSyn/year
in perimenopause:
13% for every 1-SD decrease
1.45 (95%CI 1.35-1.56)
in SHBG level*
Janssen I et al Arch Intern Med 2008;168(14):1568-75

14. Body fat distribution and
Metabolic Syndrome
Exclusion criteria
Diabetes, IHD, hypertension or
chronic disease
Matched for BMI use of OCP or HRT
Medications affecting body
Obesity clinic (Istanbul) composition/metabolism
Retrospective
Premenopausal Postmenopausal
n= 405 n= 405
Overweight/obese (BMI>27) Overweight/obese (BMI>27)
mean BMI 37.8 + 6.9 mean BMI 37.7 + 6.8
regular cycles abnormal menses x 12 mos
FSH <30 IU/L FSH >30 IU/L
Weight stable x 6 mos Excluded women with premature
menopause
Normal resting ECG
Osbey et al Endoc J 2002;49(4):503-9

15. Postmenopausal women had
more intra-abdominal fat
Matched for BMI
Premenopausal Postmenopausal p
n = 405 n = 405
Age 33.28 + 7.62 52.36 + 7.50 <0.001
Weight (kg) 92.0 + 17.5 91.2 + 16.0 NS
Height (cm) 155.9 + 5.3 155.6 + 5.8 NS
BMI (kg/m2) 37.83 + 6.91 37.77 + 6.84 NS
Waist circ (cm) 99.19 + 13.45 103.34 + 13.20 <0.001
Hip circ (cm) 123.10 + 13.10 123.83 + 13.09 NS
WHR 0.80 + 0.07 0.84 + 0.08 <0.001
IAF (L) 3.19 + 1.42 3.97 + 2.17 <0.001
Osbey et al Endoc J 2002;49(4):503-9

16. MetSyn components higher
in postmenopausal women
Matched for BMI
Premenopausal Postmenopausal p
n = 405 n = 405
Age 33.28 + 7.62 52.36 + 7.50 <0.001
Systolic BP (mm Hg) 135.12 + 26.79 148.24 + 29.77 <0.001
Diastolic BP (mm Hg) 87.70 + 15.08 91.79 + 15.71 <0.001
Glucose (mg/dL) 99.41 + 19.19 109.68 + 33.62 <0.001
Uric acid (mg/dL) 4.34 + 1.12 4.78 + 1.47 <0.001
Cholesterol (mg/dL) 202.33 + 37.09 232.22 + 43.22 <0.001
HDL-C (mg/dL) 45.32 + 10.89 47.24 + 10.38 0.016
Triglyceride (mg/dL) 152.28 + 74.93 172.68 + 79.97 <0.001
Osbey et al Endoc J 2002;49(4):503-9

17. Increase in abdominal fat
and unfavorable risk factors
despite unchanged total
body weight and BMI during
menopause transition
Menopause
Osbey et al Endoc J 2002;49(4):503-9

18. e the major determinant of the metabolic
Changes in LDL with menopause
high amounts of visceral fat have an excess
ar mortality and associated metabolic abnor- Postmenopausal women have higher to
Unclear whether menopause is a CV risk
When Pascot et al. (32) matched women for LDL cholesterol, triglycerides (TG), and
factor for all women or only those with a
by CT scan) and menopausal status, the dif-
y found in very low density lipoprotein
[Lp(a)] levels and lower HDL cholesterol l
menopausal women (38 – 40). Although elev
genetic predisposition to central obesity
DL, large buoyant HDL2 particles, LDL par-
glucose, C peptide, and blood pressure were
a component of the metabolic syndrome, LDL
by 10 –20% (23, 41) with menopause, and the
action of genetic and environmental factors influences the manifestation of the metabolic syndrome.
t (IAF) are associated with increased insulin resistance (IR) and FFA levels, and decreased adiponec
eased secretion of apo B-containing particles, leading to hypertriglyceridemia and increased HL activity
mall dense LDL particles and a reduction in the large antiatherogenic HDL2 particles.
Carr M et al JCEM 2003;88:2404-11

19. Epidemiologic data
Central fat distribution
related to adverse
psychological states
(i.e. depression and anxiety)
and to social difficulties
(i.e. unemployment and divorce)
Epel E et al Psychosomatic Med 2000;62:623-32

20. Depressive Symptoms
and Stressful Life Events
Predict MetSyn
Healthy Women Study cohort
n = 432; 15-year follow-up
Enrolled at 3-y follow-up
254 (58.8%) premenopause
63 (14.6%) perimenopause Psychosocial measures
115 (26.6%) menopause Beck Depression Inventory
Framingham Tension Scale
Had MetSyn components at Spielberger Trait Anxiety Q
3-yr follow-up and at least Spielberger Anger Q
one later examination Perceived Stress Scale
Raikkonen et al Diabetes Care 2007;30:872-7

21. Psychosocial Factors and MetSyn
Prevalence of MetSyn (ATP III) over 15-y follow-up
Depressive None/mild vs at least
Trait anger one very severe
symptoms
OR 1.40 stressful life event
OR 1.39 (1.13-1.74)
(1.11-1.74) OR 1.84 (1.20-2.81)
Framingham
Trait anxiety
tension
OR 1.03
OR 1.27 (0.83-1.28)
(1.03-1.57)
Perceived Adjusted for age, physical
activity, alcohol
stress consumption, current
OR 1.19 smoking status, use of
(0.96-1.47) HRT and level of education
Raikkonen et al Diabetes Care 2007;30:872-7

22. Stress and Body Shape
Hypothesis:
Greater vulnerability to stress increases exposure to
stress-induced cortisol ➜ central fat deposition
Psychological/
Do women with
cognitive measures:
greater central fat • Coping
(high WHR) adapt less • Mood
effectively to repeated • Rosenberg Self-
Esteem Scale
stress over time than
those with low WHR? Salivary cortisol
Epel E et al Psychosomatic Med 2000;62:623-32

23. serve as a confounding factor. Whereas overweight
women will inevitably have greater central fat as a
WHR <0.75 WHR >0.79
result of their excess fat, lean women are less likely to Trier Social
have central fat. One possible contributor to central fat
n = 29 n = 30 Stress Test
45 mins/ Arithmetic
session Serially subtract a
prime number
Stress
Day 1 from a large
session 1 number
Stress
Day 2 Visuospatial
session 2
puzzle
Replicate picture
Stress
Day 3 designs with
session 3 blocks
Control Speech
Day 4
session Convince
committee that
she is best job
applicant
Epel E et al Psychosomatic Med 2000;62:623-32

24. vivo, visceral fat deposits increased in a S. EPEL et a
E. dose-depen-
dent manner in rats and primates randomly assigned v
to a chronic stress condition (40, 41). In vitro, cortisol d
weight women, had we been able to use a more accu
increases lipoprotein lipase (a fat-storing enzyme) in t
rate measure of visceral fat.
fat tissue but has an especiallythat genetics may playi
It is also important to note exaggerated effect on
visceral the tissue (11).
role in fat stress– central fat relationship, although w f
did not examine this in the current study. Genetics ca v
account for up to AND of the variance in fat distribu
CONCLUSIONS 50% IMPLICATIONS
tion (36). That leaves another 50% of the variance theb
Although our findings are strictly correlational, to
shaped by environmental influences. There are als
psychological and cortisol data are consistent with the
hypothesis that greater psychological copingreactivity p
genetic influences on life stress and stress with stres
contributeandcentral fatreactivity (39), so it is possibl
(37, 38) to cortisol among lean women. The con- h
sistency of findings is striking: Vulnerabilitygeneticall
that stress reactivity and central fat are to stress c
linked.
was noted across both psychological and physiological s
measures among women with amanipulations of stres
Nevertheless, experimental high WHR. There is w
growing causal relationship between stress and fat dis
show a recognition that overexposure to cortisol can m
have pathophysiological consequences onof genetics. I
tribution in animal models, regardless many organ g
systems (42), stress-inducedincreased in a dose-depen
vivo, visceral fat deposits damage that has been la- h
beled manner in rats and primates randomly assigne
dent “allostatic load” (43). Central fat among lean s
to a chronic stress condition (40, 41). In vitro, allo- b
women may serve as an indicator of one type ofcortiso
increases physical lipase resulting from lack of w
static load,lipoproteindamage (a fat-storing enzyme) i
High-WHR vs low-WHR women
fat tissue to stress, that can eventually result in dis- s
adaptation but has an especially exaggerated effect o
visceral Thus, lean women with a high WHR may be a
ease (43). fat tissue (11).
greater threat appraisal
at higher risk of disease for two known and likely e
(p=0.030)
CONCLUSIONS greater exposure to cortisol and a
interrelated factors, AND IMPLICATIONS
exerted increasingly less effort
possible metabolic aberrations associated with central i
Although our findings are strictly correlational, th
fat distribution, such as greater insulin resistance (2). p
over time
psychological and cortisol data are consistent with th
(p=0.05)
Only longitudinal and genetic studies will deter- f
hypothesis that greater life stress and stress reactivit
mine conclusively whether stress and central fat, with
made more mistakes
its related metabolic profile, are causally related con
contribute to central fat among (p=0.002) The or m
lean women.
parallel phenomena. is striking: Vulnerability to stres
sistency of findings Future research needs to better i
was noted across both psychological and physiologica
define levels of risk and appropriate treatments based p
not only onamonggirth but also Medhigh WHR. causes d
measuresE one’s women with a the multiple There i
Epel et al Psychosomatic on 2000;62:623-32
of central recognition that overexposure to cortisol ca
growing fat, such as genetics, behavior, general obe- n

25. Cross-sectional data
Stress-induced cortisol secretion
may contribute to central fat:
link between psychological stress
and risk for disease
Epel E et al Psychosomatic Med 2000;62:623-32

26. Androgen
Central Metabolic
predominance
(Menopausal obesity Syndrome
transition)
Environmental
influence
Genetic
predisposition

27. Metabolic Syndrome in Community-based sample
Copenhagen
postmenopausal women Postmenopausal women
and CV mortality n = 557 (48-76 years)
8.5 + 0.3 y follow-up
Tanko et al Circulation 2005;111:1883-90

28. Enlarged waist with EWET confers 4.7-fold*
(95%CI 2.2-9.8; p<0.001)
elevated triglycerides increased risk of
(EWET) and CV mortality fatal CV events
* adjusted for age, smoking and LDL-C
Tanko et al Circulation 2005;111:1883-90

29. What should be done about it?
Identify women at
risk for MetSyn.

30. Screening for CV risk in Perimenopause
Assess all perimenopausal
women seeking medical
help for menopausal
symptoms for risk of
‣ developing CVD
‣ complications in the presence
of existing disease
Management of Cardiovascular Risk in the Perimenopausal Woman: A Consensus Statement of
European cardiologists and gnyecologists.Collins et al Eur Heart J 2007;28:2028-40

31. Menopausal Symptoms and CV Risk Factors
Eindhoven Perimenopausal Osteoporosis Study cohort
n = 5523 women aged 46 to 57 years
Self-reported data
Do women with Night sweats 38%
vasomotor symptoms Flushing 39%
differ from those Measurements
without with respect total cholesterol
to CV risk factors? blood pressure
BMI
Gerrie-Cor et al Hypertension 2008;51:1492-8

32. Menopausal Symptoms and CV Risk Factors
Eindhoven Perimenopausal Osteoporosis Study cohort
n = 5523 women aged 46 to 57 years
Women with flushing
↑ cholesterol (0.27 mmol/L [95%CI 0.15-0.39])
↑ BMI (0.60 kg/m2 [95%CI 0.35-0.84])
↑ SBP (1.59 mm Hg [95%CI 0.52-2.67]) Hypercholesterolemia
↑ DBP (1.09 mm Hg [95%CI 0.48-1.69]) OR 1.52
(95%CI 1.25-1.84)
Hypertension
OR 1.20
(95%CI 1.07-1.34)
Gerrie-Cor et al Hypertension 2008;51:1492-8

33. What should be done about it?
Address the obesity.

34. Abdominal Obesity
NCEP ATP III (Waist circ.)
Men >102 cm (40 in)
Women >88 cm (>35 in)
IDF (Waist circ.)
Men >90 cm
Women >80 cm

35. Nutritional Risk and MetSyn in Women
Selected macronutrients
Framingham Offspring-Spouse Study • Energy
300 healthy women (aged 30-69 y) free of • Protein
MetSyn risk factors at baseline • MUFA
• PUFA
12-y follow-up
Risk nutrients Protective
Tertiles of nutritional • Total fat nutrients
risk based on intake • Saturated fat • CHO
Dietary fiber
of 19 nutrients
•
• Alcohol
• Calcium
• Cholesterol
Outcomes: • Sodium
• Selenium
• Vit C, B6, B12, E
Abdominal obesity • Folate
MetSyn • β-carotene
Millen et al Am J Clin Nutr 2000;62:623-32

36. Age-adjusted proportions of women who
complied with NCEP-ATP III dietary guidelines
Nutritional risk tertile
100
1
2
3
75
% 50
25
0
Saturated fat Total fat CHO Fiber CHON Cholesterol
<7% 25-35% 50-60% 20-30 g/d 15% <200 mg/d
Millen et al Am J Clin Nutr 2000;62:623-32

37. Nutritional Risk and MetSyn in Women
Nutritional Risk Score Tertile
1 2 3
Outcome (n = 91) (n = 109) (n = 100)
Abdominal obesity RR 1.1 RR 2.3
1.0 (ref)
(WC >88 cm) (95%CI 0.6-1.9) (95%CI 1.2-4.3)
Metabolic RR 0.8 RR 3.0
1.0 (ref)
Syndrome (95%CI 0.3-2.5) (95%CI 1.2-7.6)
Multivariate logistic regression model adjusted for age, smoking,
physical activity and menopausal status
Millen et al Am J Clin Nutr 2000;62:623-32

38. Physical Activity and Changes in Weight and
Waist Circumference in Midlife Women
Study of Women’s Health Across the Nation cohort
n = 3064 women aged 42 to 52 years; 3-y follow-up
Change in weight and Exposure variables
waist circumference Age
absolute difference: Menopausal status
baseline and 3 years Physical activity
relative difference:
% baseline value
Sternfeld et al Am J Epidemiol 2004;160:912-22

39. Mean within-woman weight change between baseline
and year 3 Physical Activity and Weight and Waist Change 917
accdg to change in level of sports/exercise
Study of Women’s Health Across the Nation cohort n = 3064 women
rts/exer-
rd error, p <0.01
y, a one-
me (beta
with a
he influ-
routine
standard
within-
standard
ld/care-
ough an
sociated
c differ- Scale of 1-5
he mean for FIGUREage, baseline within-woman weight change between baseline
* Adjusted baseline 1. Mean level of sports/exercise,
race/ethnicity,(1996–1997)of chronic conditions and study according to change in the
the presence and year 3 (1999–2000) site
Ameri-
level of sports/exercise (on a scale of 1–5), Study of Women’s Health
) in the Sternfeld et al Am J Epidemiol 2004;160:912-22
Across the Nation. Results were adjusted for baseline age, baseline
er time,

40. n mean The results of the multivariable logistic regression anal-
nge in yses are summarized in table 3. In general, these results are
= 0.14Mean within-woman of the longitudinal analysis. Riskbaseline
consistent with those waist change between of
ively).
and year 3 accdg to change in level of sports/exercise
, waist
lightly
Study of Women’s Health Across the Nation cohort n = 3064 women
signifi-
n addi- p <0.05
weight,
s were
condi-
nge in
woman
nt cate-
ctivity,
Scale of 1-5
n these
evel* of
Adjusted for baseline2. Mean within-woman change in waist circumference
FIGURE age, baseline level of sports/exercise,
quares
race/ethnicity, the presence of chronic conditions and study (1999–2000) according to
between baseline (1996–1997) and year 3 site
.2, 3.3) change in the level of sports/exercise (on a scale ofet al Am Study of 2004;160:912-22
Sternfeld
1–5), J Epidemiol
.8) for Women’s Health Across the Nation. Results were adjusted for base-

41. Mean within-woman weight change between baseline
and Sternfeld et al. change in level of daily routine activity
918 year 3 by
Study of Women’s Health Across the Nation cohort n = 3064 women
Walking or daily
exercise and
p <0.01 with lower risk, bu
biking statistically sign
was
for
transportation
significantly associa
Hours of TV gain
or substantial
included in the mo
viewing
significantly associa
only 54 women ga
inclusion of this va
(data not shown).
DISCUSSION
Scale of 1-5 In this study of a
significant increase
* Adjusted for 3. Mean within-woman weight routine activity,
FIGURE baseline age, baseline level of daily change between baseline
race/ethnicity, the presence of3 (1999–2000) according to change in the
(1996–1997) and year chronic conditions and study site
ence occurred over
Sternfeld et al of risk factor for weigh
level of daily routine physical activity (on a scale of 1–5), Study Am J Epidemiol 2004;160:912-22
Women’s Health Across the Nation. Results were adjusted for base- was not, whether th

42. gain. Furthermore,
and change in daily routine activity. Of the factors associated
and waist circumfe
with substantial gain in waist circumference, the most
Mean was the 32 percent increase in risk associated with a baseline
notable
within-woman waist change between gorical change in
and increase3 by change in over time indaily routine activity activity had the le
1-kg year in weight. Increases level of the sports/ decreased their acti
Study of Women’s Health Across the Nation cohort n = 3064 women The finding that
period is consisten
Walking or tends to
that weight
p <0.05 aged adults (31, 3
biking for weight gai
woman
transportation tha
slightly lower
Healthy Women’s
Hours of TV
women, over a sim
viewing than the in
greater
year follow-up peri
imply that women
average, expect to
per year during the
initial body size, o
Scale of 1-5 was a large degree o
gain weight over ti
* Adjusted for baseline age, baseline level ofchange in waist circumference
daily routine activity, women lost at least
FIGURE 4. Mean within-woman
race/ethnicity,baseline (1996–1997) conditions3 (1999–2000) according to
between the presence of chronic and year and study site the 3-year follow-u
change in the level of daily routine physical activity (on a scale of Am J Epidemiol 2004;160:912-22 d
Sternfeld et al 1– In this study,
5), Study of Women’s Health Across the Nation. Results were domains of both s

43. Maintain or increase
physical activity in midlife
to prevent or attenuate
increase in weight and
waist circumference

44. Androgen
Central Metabolic
predominance
(Menopausal obesity Syndrome
transition)
Environmental
Genetic influence
predisposition

45. Thank You
http://www.endocrine-witch.info