Research Blog

Menopause Part 6: Cardiovascular Risk in Menopause

Welcome to part 6 of the ODX Menopause Series. This post will focus on cardiovascular disease risk in postmenopausal women, including identifying blood chemistry changes that occur.

The ODX Menopause Series

The relationship between sex hormones and CVD risk is not entirely clear and research is ongoing. Data from 2834 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated for their association with heart disease.[1]

Results indicate elevated testosterone (T) and an increased ratio of testosterone to estradiol (E2) were associated with increased risk of cardiovascular disease and heart failure.
However, the relationship between T/E2 ratio and heart failure was U-shaped, demonstrating increased risk when the ratio was extremely high or extremely low.
Higher levels of estradiol correlated with reduced risk of heart disease and both estradiol and DHEA had an inverse association with risk of heart failure.

Statistically significant differences in biomarkers at baseline included:

MESA

Postmenopause hormones & CVD risk

No CVD

CVD

Estradiol

pg/mL

pmol/L

19.9

17.9

DHEA

ng/mL

nmol/L

2.97

10.31

2.68

9.3

Bioavailable T

ng/dL

nmol/L

6.05

0.21

6.92

0.24

Total T to E2 ratio T/E2

11.55

15.42

CRP

mg/L

2.5

3.2

D-dimer

ug/mL

nmol/L

0.2

1.1

0.3

1.64

Fibrinogen

mg/dL

354

371

IL-6

pg/mL

1.3

1.6

HDL cholesterol

mg/dL

mmol/L

1.48

1.4

Exercise

MET-min/week

3630

2925

eGFR

75.8

71.5

Waist-to-hip ratio

0.91

0.94

BMI

28.5

29.6

Systolic and diastolic blood pressure

128.4 mm Hg

68.9 mm Hg

139.7 mm Hg

70.3 mm Hg

The following biomarker changes, provided by the Association for Clinical Biochemistry & Laboratory Medicine, reflect the dyslipidemia and increased cardiovascular risk associated with menopause.[2]

Cardiovascular Biomarker Patterns in menopause

Premenopausal

Postmenopausal

Total cholesterol

mg/dL

mmol/L

153.4

3.97

211.2

5.47

Triglycerides

mg/dL

mmol/L

101.1

1.14

125.5

1.42

HDL

mg/dL

mmol/L

46.7

1.2

27.7

0.7

VLDL

mg/dL

20.1

25.1

LDL

mg/dL

mmol/L

85.6

2.2

158.4

4.1

ADMA

umol/L

0.4

0.82 (non-obese)

1.34 (obese)

CRP

mg/L

2.1

3.8

A large retrospective observational study of 275 menopausal women, conducted at the Hospital Quiron Salud in Madrid, found significant differences in several metabolic biomarkers during the transition between perimenopause and postmenopause:[3]

Biomarker

Perimenopause

Postmenopause

Total cholesterol mg/dl
mmol/L

205

5.3

214

5.5

LDL-C

mg/dL

mmol/L

122.7

3.2

134

3.5

HDL-C

mg/dL

mmol/L

1.7

1.6

Triglycerides

mg/dL

mmol/L

0.86

87.5

0.99

Fasting glucose mg/dL

mmol/L

5.11

5.33

Uric acid

mg/dL

mmol/L

4.3

0.26

4.6

0.27

Calcium

mg/L

mmol/L

23.5

23.8

Vitamin D 25(OH) ng/mL

nmol/L

25.8

64.4

28.6

71.4

TSH
mIU/L

1.3

1.7

Lipids

Hormonal changes that occur during the menopausal transition appear to trigger dysregulation of lipid metabolism including alterations in circulating lipoproteins and triglycerides, and decreased beta oxidation of fatty acids. Combined with excess adipose tissue, these changes contribute to increased synthesis of adipocytokines, proinflammatory cytokines, reactive oxygen species, lipid peroxidation, insulin resistance, and ultimately CVD and type 2 diabetes if not addressed effectively.[4]

Adiposity itself is associated with cardiovascular risk. Total fat mass appears to directly affect circulating estrogen, which is relatively higher in obese versus non-obese menopausal women. Though estradiol in general is considered to be cardioprotective, higher levels in conjunction with obesity may reflect increased CVD risk. A cross-sectional study of 101 postmenopausal Caucasian women not taking hormone therapy observed that higher levels of adiposity in postmenopausal women were associated with:[5]

Increased circulating estrogens (E1 and E2)
Increased VLDL-cholesterol, VLDL- and HDL-triglycerides, hs-CRP, IL-6
Increased insulin resistance
Decreased levels of adiponectin, insulin sensitivity, and HDL-cholesterol

Mean serum estradiol correlated significantly with adiposity

- 3.26 pg/mL (12 pmol/L) Normal weight, 19 kg adipose tissue
- 4.55 pg/mL (17 pmol/L) Overweight, 28 kg adipose tissue
- 8 pg/mL (29 pmol/L) Obese, 39 kg adipose tissue

Cross-sectional studies confirm that observed serum lipid changes are associated with menopause and not just with aging. These changes include an increasingly atherogenic profile that includes more smaller, dense LDL particles, increased intermediate density lipoproteins, LDL, remnant and LDL cholesterol, and elevated glycA, a systemic inflammatory marker.[6]

Research suggests that the concentration of small dense LDL particles can increase by 30-49% in menopause. Despite a general decline in HDL, smaller denser HDL particles increase, compromising reverse cholesterol transport. [7]

The 2020 European Menopause and Andropause Society (EMAS) clinical guide for menopausal women with dyslipidemia notes that cardiovascular risk is greatest in those experiencing early menopause (before age 45). This risk is associated with adiposity, insulin resistance, hyperglycemia, and an atherogenic lipid profile characterized by increased triglycerides and total and LDL-cholesterol, and decreased HDL-cholesterol.[8]

A 5-6% reduction in LDL-C, along with a 3% increase in HDL-C can improve CVD outcomes according to a number of published meta-analyses.[9]

Women’s Health Across the Nation Study

The Women’s Health Across the Nation (SWAN) study of 2659 women noted alterations in serum lipids observed in the peri- and postmenopausal period.[10]

Total and LDL cholesterol were lowest, and HDL-C was highest in the highest quartile of estradiol.
Levels of total cholesterol, LDL cholesterol, triglycerides, and lipoprotein(a) peaked during the late perimenopausal and early postmenopausal period.
Average cholesterol increased by 9.33 mg/dL (0.24 mmol/L) during the transition from pre- to late-perimenopause whereas normal aging of 4.84 years was only associated with an increase of 6.52 mg/dL (0.17 mmol/L).
Researchers suggest lipid changes over time are attributable to the mean 33.5 pg/mL (123 mmol/L) reduction in estradiol and the mean 34.8 IU/L increase in FSH that occurs during the transition from premenopause to late perimenopause.

SWAN[11]

Pre-meno-pausal

Early peri-meno-pausal

Late peri-meno-pausal

Early post-meno-pausal

Late post-meno-pausal

Estradiol less than 21.45 pg/mL

78.74 pmol/L

Estradiol greater than

78.62 pg/mL

288.61 pmol/L

Total cholesterol mg/dL

mmol/L

196.7

5.09

197.4

5.11

205.5

5.32

206.3

5.34

205.2

5.31

202

5.23

196.2

5.08

LDL-C

mg/dL

mmol/L

116.3

3.01

115.5

2.99

121.7

3.15

123.4

3.2

123.1

3.19

120.5

3.12

113.9

2.95

HDL-C

mg/dL

mmol/L

57.7

1.49

58.4

1.51

59.6

1.54

58.7

1.52

57.7

1.49

57.9

1.50

59.0

1.53

Lipoprotein (a)

mg/dL

30.3

1.08

30.1

1.07

32.1

1.15

30.9

1.1

30.3

1.08

30.4

1.09

30.3

1.08

Triglycerides

mg/dL

mmol/L

100.2

1.13

103.3

1.17

105.8

1.2

106.4

1.2

106.4

1.2

104.3

1.18

102.0

1.15

A cross-sectional study of 444 postmenopausal women revealed a significant association between severity of symptoms and serum triglycerides, testosterone, and progesterone.[12]

Elevated triglycerides were associated with severe symptoms

- Past research also notes elevated triglycerides correlate with depression, decreased sexual desire, dry skin, and increased sweating.

High levels of testosterone were associated with severe psychological symptoms and total MRS scores.

Low progesterone was associated with severe symptoms.

Decreased progesterone may be associated with increased urogenital, psychological, and total menopausal symptom scores.

References

[1] Zhao, Di et al. “Endogenous Sex Hormones and Incident Cardiovascular Disease in Post-Menopausal Women.” Journal of the American College of Cardiology vol. 71,22 (2018): 2555-2566. doi:10.1016/j.jacc.2018.01.083

[2] Honour, John W. “Biochemistry of the menopause.” Annals of clinical biochemistry vol. 55,1 (2018): 18-33. doi:10.1177/0004563217739930

[3] Inaraja, Veronica et al. “Lipid profile changes during the menopausal transition.” Menopause (New York, N.Y.) vol. 27,7 (2020): 780-787. doi:10.1097/GME.0000000000001532

[4] Ko, Seong-Hee, and Hyun-Sook Kim. “Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women.” Nutrients vol. 12,1 202. 13 Jan. 2020, doi:10.3390/nu12010202

[5] Marchand, Geneviève B et al. “Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women.” American journal of physiology. Endocrinology and metabolism vol. 314,5 (2018): E448-E456. doi:10.1152/ajpendo.00293.2017

[6] Wang, Qin et al. “Metabolic characterization of menopause: cross-sectional and longitudinal evidence.” BMC medicine vol. 16,1 17. 6 Feb. 2018, doi:10.1186/s12916-018-1008-8

[7] Ko, Seong-Hee, and Hyun-Sook Kim. “Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women.” Nutrients vol. 12,1 202. 13 Jan. 2020, doi:10.3390/nu12010202

[8] Anagnostis, Panagiotis et al. “Menopause symptom management in women with dyslipidemias: An EMAS clinical guide.” Maturitas vol. 135 (2020): 82-88. doi:10.1016/j.maturitas.2020.03.007

[9] Baranska, Agnieszka et al. “Effects of Soy Protein Containing of Isoflavones and Isoflavones Extract on Plasma Lipid Profile in Postmenopausal Women as a Potential Prevention Factor in Cardiovascular Diseases: Systematic Review and Meta-Analysis of Randomized Controlled Trials.” Nutrients vol. 13,8 2531. 24 Jul. 2021, doi:10.3390/nu13082531 [R}

[10] Derby, Carol A et al. “Lipid changes during the menopause transition in relation to age and weight: the Study of Women's Health Across the Nation.” American journal of epidemiology vol. 169,11 (2009): 1352-61. doi:10.1093/aje/kwp043

[11] Derby, Carol A et al. “Lipid changes during the menopause transition in relation to age and weight: the Study of Women's Health Across the Nation.” American journal of epidemiology vol. 169,11 (2009): 1352-61. doi:10.1093/aje/kwp043

[12] Kaya, Cihan et al. “The relation among steroid hormone levels, lipid profile and menopausal symptom severity.” Journal of psychosomatic obstetrics and gynaecology vol. 38,4 (2017): 284-291. doi:10.1080/0167482X.2017.1321633

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