Estrogen, Cardiovascular Risk, and the Endothelium

In 2020, nearly half (48%) of Americans struggle with a vascular complication or heart disease.¹ That includes hypertension, Type 2 diabetes, and hypercholesterolemia. Women undergoing menopause have a sharp increase in that risk.² In fact, according to the CDC, heart disease is the #1 cause of death for women,³ primarily post-menopausal women. Not only that, but traditional risk factors are less predictive of cardiovascular risk for women than for men.⁴

Despite these staggering statistics, many women are unaware of their cardiovascular risk. Studies have shown the following: 

• Less than half of women report feeling informed about their cardiovascular disease risk.⁵
• Only 53% of women would call 911 if they thought they were experiencing a heart attack.⁵ 
• Major coronary events also present very differently in women, and may be overlooked by the patient or the clinician.⁶

The cardioprotective effects of estrogen have been well known for some time and may explain the lower incidence of heart disease in premenopausal women. Vascular and hormonal systems are tightly interwoven and affect one another. This article explores the connection between estrogen and endothelial health.

Menstrual cycles and vascular function

A critical structure in the blood vessels is the endothelial glycocalyx (or EGX). The EGX is the micro-thin, slippery inner lining of each blood vessel. A dense, healthy EGX is correlated with improved health, particularly cardiovascular.

A landmark study evaluated biomarkers for EGX health in premenopausal women, at 3 stages of their menstrual cycle.⁸ The study found dramatic changes at each timepoint. Estrogen seemed to reduce negative biomarkers, likely protecting the EGX, while progesterone had a more detrimental effect.⁸ Estrogen’s protective effect on the EGX may account for at least some of its cardioprotective nature. 

Menopause and cardiovascular risk factors

With that in mind, what happens during menopause, as estrogen levels decline?

In menopausal women, hot flashes have been correlated with endothelial dysfunction.⁹ This was true even comparing to age-matched (but not menopausal) controls.⁹ Endothelial dysfunction often precedes vascular dysfunction and cardiovascular conditions.

Importantly, hot flashes have recently been associated with increased cardiovascular risk factors like hypercholesterolemia and hypertension.¹⁰ Another study suggests that younger women (40-53) with hot flashes may have more pronounced endothelial dysfunction.¹¹

Another key element for women’s cardiovascular risk is uncontrolled hypertension. In one study, 56% of women with hypertension did not have their blood pressure under control.¹² As estrogen declines in menopause, hypertension increases.¹³ For women, even prehypertension increases cardiovascular risk more than smoking -- including a shocking 93% increase in stroke risk.¹²

Hypertension damages the EGX.¹⁴ The EGX also harbors anti-coagulation factors,¹⁵ so plausibly could be involved both in the increase in risk as well as poor outcomes.

These estrogen-vascular interactions are complex, and can be modulated by several other factors.¹⁶ The thorny debate around hormone replacement therapy is beyond the scope of this article, though research is ongoing.¹⁷

Consider EGX health to support vascular health

The endothelial glycocalyx is essential for vascular health, especially in menopausal women. Identifying women at risk of endothelial dysfunction and communicating that risk is essential. Supporting post-menopausal women’s vascular systems can make a difference.

The dynamic nature of the EGX makes it both easily damaged and treatable. When considering vascular health, supporting this critical structure just makes sense.

References

1. Virani Salim S., Alonso Alvaro, Benjamin Emelia J., et al. Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association. Circulation. 2020;141(9):e139-e596. doi:10.1161/CIR.0000000000000757

2. Rosano GM, Vitale C, Marazzi G, Volterrani M. Menopause and cardiovascular disease: the evidence. Climacteric. 2007 Feb;10 Suppl 1:19-24. doi:10.1080/13697130601114917

3. CDC. Women and Heart Disease. Centers for Disease Control and Prevention. Published January 31, 2020. Accessed October 22, 2020. https://www.cdc.gov/heartdisease/women.htm

4. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297(6):611-619. doi:10.1001/jama.297.6.611

5. Mosca L, Mochari-Greenberger H, Dolor RJ, Newby LK, Robb KJ. Twelve-year follow-up of American women's awareness of cardiovascular disease risk and barriers to heart health. Circ Cardiovasc Qual Outcomes. 2010 Mar;3(2):120-7. doi:10.1161/CIRCOUTCOMES.109.915538

6. Sinatra ST. “Chapter 14, Women and Heart Disease Special Considerations.” In Nutritional and Integrative Strategies in Cardiovascular Medicine. Eds Sinatra ST, Houston MC. CRC Press; 2015.

7. Menazza S, Murphy E. The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System. Circ Res. 2016;118(6):994-1007. doi:10.1161/CIRCRESAHA.115.305376

8. Hulde N, Rogenhofer N, Brettner F, Eckert NC, Götzfried I, Nguyen T, Pagel JI, Kammerer T, Hofmann-Kiefer KF, Schelling G, Dendorfer A, Rehm M, Thaler CJ. The CYCLOCALYX study: Ovulatory cycle affects circulating compartments of the endothelial glycocalyx in blood. Am J Reprod Immunol. 2018 Jan;79(1). doi:10.1111/aji.12767

9. Bechlioulis A, Kalantaridou SN, Naka KK, et al. Endothelial Function, But Not Carotid Intima-Media Thickness, Is Affected Early in Menopause and Is Associated with Severity of Hot Flushes. J Clin Endocrinol Metab. 2010;95(3):1199-1206. doi:10.1210/jc.2009-226

10. Gast GC, Grobbee DE, Pop VJ, Keyzer JJ, Wijnands-van Gent CJ, Samsioe GN, Nilsson PM, van der Schouw YT. Menopausal complaints are associated with cardiovascular risk factors. Hypertension. 2008 Jun;51(6):1492-8. doi:10.1161/HYPERTENSIONAHA.107.106526

11. Thurston RC, Chang Y, Barinas-Mitchell E, et al. Physiologically assessed hot flashes and endothelial function among midlife women. Menopause. 2017;24(8):886-893. doi:10.1097/GME.0000000000000857

12. Pimenta E. Hypertension in women. Hypertension Research. 2012;35(2):148-152. doi:10.1038/hr.2011.190

13. Smith P. “Chapter 15, Hormones and their effects on the cardiovascular system.” In Nutritional and Integrative Strategies in Cardiovascular Medicine. Eds Sinatra ST, Houston MC. CRC Press; 2015.

14. Facchini L, Bellin A, Toro EF. Modeling Loss of Microvascular Wall Homeostasis during Glycocalyx Deterioration and Hypertension that Impacts Plasma Filtration and Solute Exchange. Curr Neurovasc Res. 2016;13(2):147-155. doi:10.2174/1567202613666160223121415

15. Gouverneur M, Berg B, Nieuwdorp M, Stroes E, Vink H. Vasculoprotective properties of the endothelial glycocalyx: effects of fluid shear stress. J Intern Med. 2006;259(4):393-400. doi:10.1111/j.1365-2796.2006.01625.x

16. Chakrabarti S, Morton JS, Davidge ST. Mechanisms of estrogen effects on the endothelium: an overview. Can J Cardiol. 2014 Jul;30(7):705-12. doi:10.1016/j.cjca.2013.08.006

17. Lopez-Pier MA, Lipovka Y, Koppinger MP, Harris PR, Konhilas JP. The clinical impact of estrogen loss on cardiovascular disease in menopausal females. Med Res Arch. 2018;6(2):1663. PMID: 32149188

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