Into the Heart

Estrogen a Natural Antioxidant

Reactive oxygen species or free radicals are a type of cellular chemical energy that have a single unpaired electron in their outer orbit. Free radicals are highly reactive; unstable cells that are generated as a natural result of oxygen breakdown.

 

Oxidative stress is defined as the imbalance in favor of reactive oxygen species generation over cellular antioxidant protectors. Oxidative stress contributes to an increase in arterial blood pressure and the subsequent progression of hypertension by decreasing nitric oxide bioavailability.

 

Within the artery nitric oxide is a highly protective molecule that maintains vascular tone and reactivity.  Nitric oxide helps arteries stay relaxed and dilated. When nitric oxide is diminished arteries tend to tighten and become damaged which contributes to increased blood pressure.

 

  The hormone estrogen, (estradiol) provides natural antioxidant properties because it increases the expression of antioxidant enzymes and decreases troublesome NADPH oxidase enzyme activity and superoxide production. Estrogens have a phenolic hydroxyl group at position 3 and a methyl group at position 13. The presence of this phenol group gives estrogen its antioxidant property by neutralizing oxygen free radicals. The estrogens estriol and estradiol confer significant antioxidant activity.

 

During the menopause transition estrogen production naturally diminishes. This decrease in estrogen tends to result in an increase in oxidative stress for post menopausal women. This increase in oxidative stress (reduction in nitric oxide bioavailability) is a mechanism which places women age 45 and older at increased risk of hypertension and cardiovascular disease. Enhancing antioxidant enzyme systems and efficiency for menopausal and post menopausal women will help to compensate for the age/sex related loss of antioxidant balance.

 

In addition to enjoying antioxidant rich foods such as berries, plums, pecans, and red wine, fitness (for men and women) enhances enzymatic antioxidant efficiency. Exercise improves (upregulates) antioxidant enzyme efficiency which decreases oxidative stress which then results in enhanced (artery relaxing/protecting) nitric oxide bioavailability.

 

The University of Calgary/Canada conducted a study (noted below) specific to oxidative stress and blood pressure in post menopausal women. The results of this study demonstrated that after menopause, fitness level and regular physical activity mediate (protect) against oxidative stress by maintaining antioxidant enzyme efficiency. More specifically, hushing/blocking oxidative stress by regular physical exercise helps modulate blood pressure and cerebral vascular conductance (blood flow to the brain) after menopause. 

 

Healthy antioxidant rich foods each day, blended with regular physical activity is therapeutic to the prevention and management of hypertension for midlife women. As such, a brisk walk nurtures the soul and relaxes the arteries.

Source:

Effect of Cardiorespiratory Fitness on Vascular Regulation and Oxidative Stress
in Postmenopausal Women
Vincent Pialoux; Allison D. Brown
Hypertension. 2009; 54:1014.

Yes, Menopause Hot Flashes are Clinically Important

Hot flashes . . . a sudden feeling of heat in the face, neck or chest are experienced by eighty percent of women during the menopause transition. However, for years, perhaps decades, hot flashes have been considered as a symptom that mainly affects quality of life for menopausal women without any other clinical significance. Recently this simplified premise has been challenged.

 

The presence of hot flashes is now being associated with an elevated cardiovascular risk profile. Higher total cholesterol levels, blood pressure and body mass index are more likely in menopausal women who experience (symptomatic) hot flashes when compared to women who do not (asymptomatic) experience hot flashes.

 

The study noted below found menopausal women with moderate/severe/very severe hot flashes had significant endothelial dysfunction, as shown by reduced brachial artery flow mediated dilation and greater aortic calcification when compared with menopausal women of similar age without hot flashes (vasomotor symptoms).

 

The endothelium is the extremely thin inner lining of the artery. The endothelium protects the artery, like a glove protects the hand from harsh elements. If the endothelium becomes damaged or dysfunctional the artery can become torn and inflamed. Such damage generates a type of cellular buildup which eventually hardens and reduces blood flow within the artery.

 

Of additional importance, this study demonstrated that HDL cholesterol levels were significantly lower in women with moderate/severe/very severe hot flashes when compared with women with no/mild hot flashes. HDL cholesterol transport fats (lipids) away from the arteries. HDL also possesses artery protecting antioxidant properties. Low circulating levels of HDL cholesterol indicate increased cardiovascular risk.

 

The severity of hot flashes is clinically significant and is viable indicator (prognostic value) of arterial function and health in menopausal and post menopausal women.

 

Information presented within this website Into The Heart. com  relates how to maintain healthy HDL cholesterol and arteries.

 

Source:

Endothelial Function, But Not Carotid Intima-Media Thickness, Is Affected Early In Menopause and Is Associated with Severity of Hot Flushes.

Aris Bechliouis, Sophia N. Kalantaridou

J Clin Endocrinol Metab, March 2010, 95(3); 1199-1206

Hot Flashes, Menopause and Cardiovascular Health

Concern regarding hot flashes, menopause and cardiovascular health had been related in an earlier post on this blog. High global readership on this topic indicates more clarity would be beneficial for women with hot flash concerns. As such, the enclosed provides more perspective.

Vasomotor symptoms, hot flashes correlate with lower level of plasma antioxidant activity, an increased cardiovascular reactivity to stressful situations, elevated cholesterol, higher sympathetic nerve activity, impaired flow-mediated dilation, hypertension and a higher risk of aortic calcification.

Hot flushes are an indicator of, a marker for underlying arterial changes among otherwise healthy menopausal women. More specifically, healthy postmenopausal women with hot flashes have different cardiovascular risk factors than postmenopausal women without hot flashes.

Hot flashes are more than just bothersome, they are an indication, a message to women of potential heightened cardiovascular risk factors . . . as noted in the second paragraph.

Source:
Vasomotor symptoms and cardiovascular risk.
Climacteric. 2009;12 Suppl 1:32-5.
Gambacciani M, Pepe A.
Department of Obstetrics and Gynecology, Menopause and Osteoporosis Center,
Pisa University Hospital, Pisa, Italy

Hot Flashes a Matter of Her Heart

Emerging research suggests underlying vascular changes among women with hot flashes.

The study noted below examined associations between hot flashes and indices of subclinical cardiovascular disease including flow mediated dilation , coronary artery calcification , and aortic calcification.

Impaired flow mediated dilation is an indicator of endothelial dysfunction. The endothelium is the protective inner lining of the artery. Upon calcification arteries become easily damaged and stiff. The heart then has to pump harder and will wear out faster.

In the study noted hot flashes were associated with significantly lower flow mediated dilation and greater coronary artery and aortic calcification in age and race adjusted models.

Keep in mind pectin , the soluble fiber in prunes helps inhibit aortic calcification. Additionally, Vitamin K-2 is required for the activation of the vascular protein MGP (Matrix Gla Protein) , which is the primary inhibitor of arterial calcification. Butter and cheese produced from grass feed cows, and fermented foods contain vitamin K-2.

For postmenopausal women diminishing hot flashes is a serious matter of the heart.

From the Study of Women’s Health Across the Nation Heart Study. Participants were 492 women (35% black, 65% white) 45 to 58 years of age who were free of clinical cardiovascular disease and had a uterus and at least one ovary.

Source:
Hot Flashes and Subclinical Cardiovascular Disease
Circulation. 2008;118:1234-1240.
American Heart Association, Inc. 2008

A Hot Flash … A Burst of Oxidative Stress

During a hot flash the blood vessels close to the skin open wider than usual. This allows for more blood flow which generates a sense of warmth. Perspiration then occurs on the skin to cool down the body.

A burst of oxidative stress also accompanies a hot flash. The oxidative stress causes LDL cholesterol in the arteries to essentially brew contributing to inflamed, stiffened coronary arteries. Oxidative stress also wears down the protective inner lining of the artery: the endothelium. This leads to torn and tightened arteries.

For post menopausal women who experience ongoing hot flashes it is cardio protective to diminish the occurrence of hot flashes and counteract the bursts of oxidative stress. Berries, red peppers and prunes are high in water soluble inner cell antioxidants.

However, the oxidative stress that accompanies a hot flash effects the fat soluble membrane of the cell. Enhancing vitamin E intake will be beneficial because vitamin E is the prime cell membrane stabilizer and antioxidant. Vitamin E does not necessarily reduce hot flashes but is able to provide cellular protection from oxidative stress.

The daily reference intakes for vitamin E is 15 mg. One quarter cup a sunflower seeds has 17 mg of vitamin E. Olive oil and wheat germ oil are also good sources of vitamin E. Vitamin E also helps reduce production of thromboxane A2 which causes platelet clumping.

Source:
Influence of the presence of hot flashes during menopause on the metabolism of nitric oxide.
Med Clin (Barc). 2000 Jan 22;114(2):41-5
Leal Hernandez M, Abellan Alernan J

Hot Flashes and Systolic Blood Pressure

The hormone estrogen has a regulatory role in arterial structure and function. During the menopausal transition estrogen fluctuations, primarily diminished estrogen contributes to vasomotor symptoms: hot flashes.

While hot flashes are disruptive there is more serious reason to be concerned. According to a study noted in Menopause 2007, menopausal women with hot flashes tend to have elevated systolic blood pressure when compared to menopausal women who do not experience hot flashes. Elevated systolic blood pressure contributes to damaged, stiff arteries which increases cardiovascular risk. Torn damaged arteries stimulate a cascade of inflammatory cellular mediators which leads to arterial build-up an plaque.

The association between hot flashes and systolic blood pressure is independent of age, race/ethnicity, body mass index, and menopausal status. Hot flashes were not associated with changes in diastolic blood pressure.

Milled flaxseed, (calcium enriched & organic soy milk nice/nurturing) soy nuts, the supplement pycnogenol and soy based estrogen replacement (cream, gel or patch) are all options to help diminish hot flashes in menopausal and post menopausal women.

Source:
Hot flashes are associated with increased ambulatory systolic blood pressure.
Menopause. 2007; 14:308-315.
Gerber LM, et al.

Estrogen, Salt Sensitivity and Hypertension

Dietary salt contributes to high blood pressure by increasing blood volume. The heart has to work harder to pump thicker blood which increases blood pressure.

Women are more prone towards high blood pressure at the onset of menopause and postmenopausally. As such, evidence is accumulating in regard to the role of estrogen and high blood pressure (hypertension). A recent study by The University of Texas Health Science Center concluded that estrogen protects against high salt hypertension by attenuating (lessening) the activation of the sympathetic nervous system.

Salt sensitive and salt resistant female rats were fed a 4% NaCl diet. Blood pressure was measured by radiotelemetry. Subjects were divided into three groups: those producing estrogen, not producing estrogen, and those not producing estrogen but supplemented with estrogen replacement. After eight weeks, sympathetic nervous system activation was assessed by urinary excretion of norepinephrine, and by the blood pressure response to ganglionic blockage. Norepinephrine is a biochemical marker of sympathetic nervous system activation.

Subjects not producing estrogen had a significantly higher blood pressure 175 ± 6 mm Hg compared to subjects producing estrogen 153 ± 5 mm Hg. Estrogen replacement in salt sensitive subjects not producing estrogen prevented the increase in blood presure 152 ± 6 mm Hg.

Urinary norepinephrine was significantly greater in subjects not producing estrogen 40 ± 8 ng/ml compared to subjects producing estrogen 21 ± 2 ng/ml.  Estrogen replacement in subjects prevented the increase in norepinephrine excretion 20 ± 1 ng/ml.

In salt sensitive subjects, the fall in blood pressure with ganglionic blockage was increased in those not producing estrogen compared to those producing estrogen, which was prevented with estrogen replacement.

This study concluded that estrogen loss augments (increases), and estrogen replacement attenuates(lessens) the effect of the sympathetic nervous system to hypertension in salt sensitive subjects on a high salt diet.

Postmenopausal women naturally experience a loss of estrogen which may predispose some women to high blood pressure. A low sodium diet at midlife is beneficial to arterial health/function.

Source:
Effect of estrogen on sympathetic nervous system activation in high salt hypertension
Carmen Hinojosa-Laborde, Cindy Mehring and Teresa Craig   Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, TX
The FASEB Journal. 2008;22:941.7

Estrogen Replacement . . . earlier

The vascular endothelium is a single layer of cells lining all the blood vessels in the body. The endothelium is essential for vasodilatation in response to increases in blood flow associated shear stress: termed endothelium dependent flow mediated vasodilatation (FMD).

Several vasodilators are released by the endothelium in response to shear stress including nitric oxide and prostacyclin. A small FMD response is interpreted as indicating a low nitric oxide bioavailability and is associated with an increased risk of vascular disease and cardiac events.

Vascular endothelial and smooth muscle cells express estrogen receptors A and B.

The study indicated below, evaluated flow mediated dilatation (FMD) of the brachial artery in 134 postmenopausal women before and after acute (1 hour) and chronic (3 months) of estrogen administration (replacement).

Estrogen administration improved FMD more in women within five years of menopause, (76% acute, 74% chronic administration) than in women more than five years since menopause (45% acute, 48% chronic).

Although acute and chronic estrogen administration improved endothelial function in all women, the improvement was dependent on time since menopause: the duration of hormone deprivation.

Women who had previously used estrogen replacement also had more improved FMD (59% acute, 63% chronic) upon administration than nonusers of estrogen replacement (31% acute, 38% chronic).

Estrogen tends to exert a favorable effect on endothelial function and arterial health when estrogen replacement therapy (ERT) or HRT is initiated soon after menopause.

Keep in mind, the type/dose, time of initiation of ERT or HRT should be customized to a woman’s age, cardiovascular risk factors and pre-existing cardiovascular conditions.

Source:

Time Since Menopause Influences the Acute and Chronic Effect of Estrogens on Endothelial Function. Cristiana Vitale, Giuseppe Mercuro MD’s

Arteriosclerosis, Thrombosis and Vascular Biology. 2008;28:348

Estrogen Replacement and Blood Pressure

Postmenopausal women tend to have higher blood pressure than premenopausal women; suggesting a protective role of the hormone estrogen on blood pressure regulation. This protective effect is in part due to the inhibition or regulatory effect of estrogen on the sympathetic nervous system. Heightened sympathetic nervous system stimulation constricts blood vessels by stimulating A-1 receptors located on the surface of vascular smooth muscles.

The route of estrogen administration is a major determinant of the effect of estrogen replacement therapy (ERT) on sympathetic discharge. The study noted below found that sympathetic nervous system discharge (stimulation) decreased significantly from baseline during transdermal ERT but not during oral ERT or placebo.

The decrease in sympathetic nerve discharge achieved only with transdermal administration is not thought to be a dose related because serum estradiol concentrations achieved with oral ERT were comparable to those with transdermal ERT. However, with oral administration the liver is exposed to a supraphysiological concentration of estrogen resulting in decreased hepatic synthesis of insulin-like growth factor-1 (IGF-1).

Administration of IGF-1 has been shown to decrease sympathetic nerve activity and blood pressure in rats. Deficiency of this growth factor is associated with sympathetic overactivity and elevated blood pressure in humans.

Of additional interest, reduction in IGF-1 induced by oral estrogen preparations is accompanied by reduced lean body mass and increased fat mass (adiposity), which is a powerful predictor of elevated sympathetic discharge and blood pressure.

Therefore, it seems plausible that during oral estrogen replacement, sympathetic overactivity related to IGF-1 deficiency and/or increased (fatty tissue) opposes the direct effect of estrogen to decrease sympathetic discharge.

Avoidance of first-pass hepatic (liver) metabolism with transdermal estrogen replacement allows the estrogen-induced sympathetic inhibition to be unopposed.

As such, the route of administration is an important consideration in optimizing the beneficial effects of estrogen replacement on blood presure and cardiovascular health.

Estrogen is also thought to act on the central nervous system by decreasing sympathetic nerve discharge, the neural stimulus for norepinephrine release from peripheral sympathetic nerve terminals. Estrogen replacement has been shown to both activate vasodilator mechanisms mediated by nitric oxide or prostacyclin and inhibit vasoconstrictor response to norepinephrine.

Sources:
Transdermal Estrogen Replacement Therapy Decreases Sympathetic Activity in Postmenopausal Women
Wanpen Vongpatanasin, MD; Meryem Tuncel, MD
Circulation. 2001;103:2903.

Estrogen Replacement, Vascular distensibility, and Blood Pressures in Postmenopausal women.
DeMeersman R, Zion AS, Giardina EGV, et al.
Am J Physiol. 1998;274:H1539–H1544.

Estrogen Nurtures the Upper Chambers of the Heart

Atrial naturiuretic peptide is a cardiac hormone produced predominantly in the atria of the heart. Atrial natriuretic peptide induces relaxation of coronary arteries, inhibition of L-type Calcium channels* in the myocardium, suppression of the renin angiotensin system and decreased sympathetic nervous system activity. These effects are protective to the cardiovascular system and are also induced by estrogen.

The atria are the two upper chambers of the heart. Estrogen receptors are expressed in the atria. There is an increased expression and secretion of atrial natriuretic peptide in response to estrogen receptor activation.

However, during the menopausal transition and for women of postmenopausal years, diminished estrogen production can offset any of the protective regulatory mechanisms provided by artrial natriuretic peptide. For menopausal and postmenopausal women such symptoms can include heart palipitations due to altered intercellular calcium handling and hypertension due to angiotensin activity and a shift in sympathovagal balance.

*L-type calcium channels are located on vascular smooth muscle, cardiac myocytes and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction (blood pressure) and cardiac myocyte contraction (heart beat).

Source:
Estrogen Receptors Activate Atrial Natriuretic Peptide in the Rat Heart
Marek Jankowski, Grazyna Rachelska
PNAS Sept 2001, Vol. 98, no 20, 11765-11770