The Decline Of Estrogen Levels Biology Essay

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Animal studies have shown that vascular smooth muscle hyperplasia and collagen biosynthesis are reduced by estrogen administration. In one clinical study, postmenopausal estrogen use was associated with significant borderline reductions in measured common carotid artery wall intimal medial thickness even after controlling for other risk factors such age, smoking, lipids, etc. (50).

In a subanalysis of the Asymptomatic Carotid Atherosclerosis Progression Study (ACAPS), women who used ERT (preparation and dose not specified) were assessed for carotid artery wall intimal-medial thickness (IMT) by carotid ultrasonography. IMT, which is a marker for atherosclerosis, appeared to be retarded and to possibly reverse in women who took estrogen without receiving lipid-lowering therapy (51).

Changes in Vascular Compliance and Blood Pressure

A newly recognized marker for hypertension and atherosclerosis is reduced vascular compliance. The latter describes the condition of the arterial wall that influences the relation between volume and pressure. In stiffer vessels, a smaller volume change will cause a greater pressure rise as compared to a normally compliant system. Vascular compliance is known to decrease with menopause.

One direct measure of vascular stiffness is the pulsatility index (PI). This represents the impedance to blood flow downstream from the point of measurement. An increase in PI is closely correlated with the time elapsed after the menopause. Decreases in arterial waveform pulsatility index in the uterine and carotid arteries have been demonstrated in postmenopausal women after chronic estrogen replacement suggesting an improvement in arterial compliance (52). In another recent study, patients were treated with estrogen and progesterone for 1 yr and a significant decrease in PI was observed at 48 wk (53). Arterial compliance is increased with pregnancy but returns to normal within 8 wk postpartum suggesting that these changes were not secondary to a change in vascular structure, but to a reduction in smooth muscle tone (56).

Premenopausal women have lower systolic blood pressure than men of a similar age. After menopause, however, systolic blood pressure tends to be higher than in age-matched males. One study has also shown that an increase in pulsatile components of blood pressure is associated with higher cardiovascular risk in postmenopausal women (55). The changes in blood pressure with menopause were explored in a study of both premenopausal and postmenopausal women who were compared with age-matched men (56). Using ultrasound/Doppler to measure vascular flow, the authors found that premenopausal women had lower systolic blood pressure in their peripheral arteries, but not in their central (i.e., carotid) artery. Males had greater peripheral blood pressure that was attributed to amplification of blood pressure from central to peripheral arteries, which increased with body height and decreased with arterial distensibility. In contrast, in postmenopausal women, arterial distensibility was similar to that of age-matched men and no longer compensated for smaller body size, resulting in a persistent increased defect of wave reflections in central arteries, and greater peripheral blood pressure (56).

In a related study, 18 women with essential hypertension were followed for 3 yr, during which time they went through menopause, to investigate whether a natural decrease in sex hormones in hypertensive women caused an increase in the stiffness of the aortic root (57). The authors found that aortic root distensibility decreased significantly in women who had gone through menopause as compared with age-matched controls, suggesting an important role for declining estrogen levels in this process.

Changes in Cardiac Function

Estrogens affect hemodynamic parameters through several different mechanisms. There is less evidence about the effects of declining estrogen levels with menopause on hemodynamic function. In one study, which followed women through the menopause transition, no significant change in echocardiographic measurements of end-diastolic and end-systolic dimensions were found after menopause. However, significant decreases in rest Doppler measurements of left ventricular contractility appeared progressively over the years after menopause in women not treated with hormone replacement therapy (58). These factors appeared to be modified with hormone replacement therapy suggesting a positive inotropic effect of estrogen (59,60).

METABOLIC CHANGES WITH MENOPAUSE

Changes in Lipid Metabolism

Several epidemiologic studies have suggested increases in levels of total cholesterol, low-density lipoproteins and triglyceride rich lipoproteins associated with menopause. He et al (2012) have reported significantly higher prevalence of elevated total cholesterol, triacylglycerols and LDL levels in post menopausal Chinese women compared to premenopausal counterparts.

In general, HDL levels are stable in the years after menopause, although there may be a small reduction in HDL2 subfraction. Presumably, these changes with menopause are secondary to reduction in endogenous hormones. This is certainly supported by the beneficial effect of postmenopausal hormone therapy on lipoprotein metabolism in postmenopausal women. Studies suggest that estrogen use is associated with elevations in high-density lipoprotein (HDL) cholesterol, especially (HDL) cholesterol, especially HDL2 ny as much as 20% and reduction in low-density lipoprotein (LDL) cholesterol by as much as 19%

An elevated Lp(a) level is independently associated with the development of CAD in women (64) as well as men. Lp(a) is a modified form of LDL to which an apolipoprotein is attached. Its genetic structure is similar to plasminogen and, thus it interferes with the binding of plasminogen to sites of cells and molecules. Levels of Lp(a) are primarily determined by gentic and, as such, there are no abrupt changes in Lp(a) with menopause. However, estrogen theraphy appears to reduce Lp(a) levels. An elevated plasmahomocysteine level is an independent risk factor for CAD especially premature atherosclerosis. Levels are known to increase in both genders with age. After menopause, fasting homocysteine levels may increase or stay the same (65). Thus, the impact of declining estrogen levels on homocysteine levels is unclear.

In animal studies, estrogen appears to interfere with cholesterol deposition in the arterial wall (66) and in laboratory studies to reduce arterial smooth muscle cells proliferation (29). Oxidative modification of LDL cholesterol may be an important step in atherogenesis. In animal studies, the oxidized form of LDL appears to be more effective than inactive LDL in impairing endothelium-dependent vasodilation. One recent study suggests that endothelium mediated vasodilation is improved with lipid lowering drugs in patients with elevated cholesterol particularly if the lipid lowering therapy lowers rates of LDL oxidation (67). In vitro studies suggest that 17- estradiol appears to inhibit LDL oxidation and reduce cholesterol ester formation (68). In one study, 17- estradiol administration significantly reduced the oxidation of LDL cholesterol from postmenopausal women (69).

Changes in Clotting

Certain hemostatic variables change with menopause with a potential impact on both thrombosis and fibrinolysis. After menopause, fibrinogen levels increase as do levels of factor VII and antithrombin III. Higher levels of PAI-1 an antagonist of fibrinolysis in humans, have been noted in postmenopausal women in the Framingham Offspring Study (71). Studies of HRT in postmenopausal women suggest a decrease in fibrinogen (72), and a decrease in PAI-1 (73). Animal studies also suggest that estrogen inhibits platelet aggregation.

Symptoms of Vasomotor Instability

Symptoms of vasomotor instability include palpitations and, in a small percentage of women, symptoms of chest pressure. Although they occur most often in conjunction with hot flashes, an increase in palpitations can be seen in the absence of other symptoms. The severity of these cardiac symptoms appears to be related to the severity of the hot flashes (74). Vasomotor symptoms and associated cardiac symptoms are more severe in patients who experience a sudden drop in their estrogen level (e.g., surgical menopause). In one longitudinal study of 200 perimenopausal women from Scandinavia, palpitations figured prominently in the symptomatology in association with other vasomotor complaints (75). In another survey of 501 women, 1220% of those who were postmenopausal noted pressure in chest and 3647% noted a change in heart rate in association with their hot flashes (76).

Effects on Glucose Metabolism

Estrogens have been known to affect glucose metabolism which is evident by presence of estrogen receptors in pancreatic islets. Tiano and colleagues (8) examined the role of estrogen in pancreatic β cells based on their observations that in many rodent models of diabetes and dysregulated glucose homeostasis, the females remained relatively protected with respect to the pancreatic β cell function. Tiano et al. (8) posited that ovarian hormones may provide protection

against pancreatic β cell abnormalities. These authors focused on what happens in males when supplemented with estrogens. In the first series of experiments,

the authors found that treating male Zucker diabetic fatty rats with 17 β estradiol suppressed the synthesis and accumulation of fatty acids and protected against pancreatic β cell failure. Furthermore, they demonstrated that the antilipogenic actions of estrogens were replicated with pharmacological activation of ER β. The authors looked at a host of glucose parameters and in every case found that estrogenic supplementation reversed the effects in the dysregulated glucose homeostasis in diabetic fatty rats. In addition, deletion of ER β from the pancreas prevented the reduction of lipid synthesis by estrogens and increased islet lipid accumulation and β cell dysfunction in response to a high-fat diet. The authors demonstrated that estrogenic activation inhibited β cell lipid synthesis by suppressing the expression of fatty acid synthase through a non classical (NERKI) pathway that was dependent on activated (pSTAT3) STAT3. Finally, they demonstrated that deletion of STAT3 from the pancreas curtailed ER β mediated suppression of lipid synthesis.

Iron Deficiency

Anemia has been emerging as potent risk multiplier of mortality risk in middle-age population. Earlier considered to be merely a disease marker, it is now envisaged as having profound implications as a comorbid factor for other illnesses while posing a serious health risk on its own. Anemic patients have a shorter survival than their nonanemic, age-matched counterparts4 and anemia is also an independent risk factor for mortality in heart disease5, cancer6, renal disease7 and HIV infection8

The prevalence of anemia according to NHANES III (1988-1994), in US women of age-group 50-64 years, was reported to be 6.8% as compared to 4.4% in men and 8.5% in 65-74 year old women and further 10.3% in 75-84 year old females. However, the prevalence of anemia continues to be higher in pre-menopausal women than in those experiencing menopause (11% in pre-menopausal versus 19% in perimenopausal women in US, 2002) 9. Prevalence in Indian middle-aged women needs to be studied, due lack of data in this regard and especially in view of emergence of anemia as an independent risk factor for heart disease, which affects women in middle-age.

Fig 2.8 Cascade of Metabolic Events due to Estrogen Deficiency

C:\Users\Public\Documents\RESEARCH WORK\PhD\Review\Images\Cascade of Metabolic Events due to Estrogen Deficiency.jpg

Overweight and Obesity

World Health Organization (WHO) defines overweight as having a Body Mass Index (BMI) >25kg/m2 and obesity as BMI > 30kg/m2. There are approximately 350 million obese people and over 1 billion overweight people in the world. Over all about 2.5 millions deaths are attributed to overweight/obesity worldwide. Prevalence of obesity in India, as estimated by the National Family Health Survey 3 10 in rural and urban women, was reported to be highest in age-group of 40-49 years: 6.4% as compared to only 2.3% in males in the same age group; followed by 3.9% in 30-39 year age group (men 1.8%) and 1.2% in 20-29 year age group (men 0.7%). Similar trends were reported in case of overweight prevalence: highest prevalence was in women in 40-49year age group (23.7%) compared to 15.2% in men of same age group; followed by 17.4% in 30-39 year age group compared to 13% in men and 8.2% in 20-29 years age group compared to 6.5% in men. Thus, overweight and obesity is prevalent highest in women at and around menopausal age.

Diabetes Mellitus

WHO (2000) estimates the global prevalence of Diabetes to be 171 million and India contributes 31.7 million cases. The National Health Interview Survey in US (2003) mapped diabetes prevalence and found a systematic increase in prevalence with age in both the sexes: 2.8% in 35-39 years, 6.5% in 45-49 years, 11.7% in 55-59 years and 15.1% in 65 years and above. In India, National Urban Diabetes Survey 11 reported the national prevalence of diabetes (FBS > 125) to be 8.5% in women aged 34-35 years, which increased to 19.7% in 45-49 years and 28.7% in 54-59 years. Jaipur Heart Watch 3 12 estimated prevalence in Punjabi Bhatia community in urban as well as rural areas to be 1.6% in women aged 30-39 years, 12.2% in 40-49 years and 27.3% in 50-59 years and 37.8% in 60 years and more. Thus a trend of a sudden rise in prevalence of diabetes after 40 years can be noticed in Indian women.

Hypertension

Hypertension, defined as Systolic Blood Pressure (BP) higher than 120mmHg and/or Diastolic BP higher than 80mmHg, is the highly prevalent threat to cardio-vascular health. Globally, 26.1% of women have hypertension 13. The Jaipur heart Watch 3 12 reported the prevalence of hypertension in urban women to be 29% in 30-39 year age-group, which rose to 67.3% in 40-49 years, 72.7% in 50-59 years and reaching peak at 91.2% in 60 years and above age group.

Dyslipidemia

Dyslipidemia is defined as total cholesterol higher than 200mg/dl, LDL-C >100mg/dl, Triacylglycerols >150mg/dl. Dyslipidemia increases rapidly in menopausal age. Percent prevalence of hypercholesterolemia (TC > 200mg/dl) in US women, as reported by National Health and Nutrition Examination Survey 14 was 16.2 in 35-39 years age group, which increased to 25.3% in 45-49 years and 31.1% in 55-59 years. In a study done in Jaipur 12, the prevalence of high total cholesterol (TC>200mg/dl) in urban and rural women was reported to be 22% in 30-39 years, 34% in 40-59 years and 42% in 60years and above.

Hypothyroidism

Subclinical Hypothyroidism (SCH), defined as TSH > 4mU/l in presence of normal free T4 (FT4) [0.9 to 1.9 ng/dL], is emerging as a yet another co-morbid factor in the family of risk factors of chronic diseases. While clinical Hypothyroidism has been known to adversely affect cardiovascular health, SCH is also argued to be associated with hypertension 15, responsible for 19.3mg/dl of total cholesterol in middle aged women and its prevalence runs as high as 7.6% in middle aged women belonging to Netherlands, as compared to only 1.9% in men of the same age group 16. According to the Rotterdam prospective cohort study 17, the prevalence (in middle aged women) was even higher: 10.8%.

WHEATGRASS - THE WONDER HERB OF AYURVEDA

Wheatgrass, hugely popular in Indian traditional healing systems, has been found to be effective in treatment of gastrointestinal disorders (Ben-Arye et al 2002). It is a popular traditional belief that eating wheatgrass confers the benefits of consuming large amounts of vegetables in a day. The composition of wheatgrass accounts for this notion: 3.5g of wheatgrass itself has 15mg chlorophyll, 1g dietary fibre, 1mg Lutein and 29mcg Lycopene, 2-8% RDA of all essential amino acids. Wheatgrass has been shown to exhibit excellent antioxidant properties. Wheatgrass extracts have been found to inhibit significantly ascorbate-Fe2+ induced lipid peroxidation in rat liver mitochondria and its free radical scavenging ability is reported to be higher than those of many natural extracts or vegetables (Kulkarni et al 2006).

Wheatgrass is found to be rich in all major three classes of bioactive compounds: Phytosterols, Viscous Polysaccharides and Polyphenols. Phytosterols, namely beta-sitosterol, campesterol, and stigmasterol were found in hexane extracts of wheatgrass, with beta-sitosterol accounting to 74% of the total phytosterols in the extract, which ranged from 834-1206 mg/kg (Dunford, Irmak and Jonnala 2009, Dunford and Edwards 2010). Polyphenol tests revealed the presence of flavonoids, triterpenoids, anthranol, alkaloids, tannins, saponins and sterols in fresh grass juice (Kothari et al 2011).Aqueous extracts of wheatgrass were found to contain gums and mucilages also, which belong to the family of viscous polysaccharides (Shirude 2011).

It has been found that wheatgrass has a lysine arginine ratio of 0.7, considered to be low compared to animal protein, with the value for casein being 1.2; and also a low methionine content of 15mg per 3.5g of wheatgrass, which is abysmally low compared to 86mg of 100ml cow's milk or other proteins of animal origin. A low lysine-arginine ratio and low methionine content have found to exert hypocholesterolemic effects (Kritchevsky 1979).The underlying mechanisms seem to be reduced absorption of cholesterol, increase in glucagon secretion and inhibition of insulin production (Sanchez 1991). The other mechanism can be suppressing the HMG CoA reductase and 7-α-hydroxylase activities through regulating hepatic glutathione concentrations (Potter and Kies 1990).

Results from a recent mouse model study (Kothari et al 2011) on wheatgrass were similar to found in this research, wherein wheatgrass juicewas administered at 5 mL/kg and 10 mL/kg in hypercholesterolemia induced Wistarrats for a period of 14 days. The supplementation resulted in dose dependent significant (p<0.05) decline in TC, TAG, LDL and VLDL levels.The researchers also looked at the fecal cholesterol excretion which was significantly enhanced (p<0.05) upon wheatgrass supplementation.

Another study in rabbit model (Das, Hakim and Mittal 2012) evaluated the effect of ethanol extract of wheatgrass hyperlipidemic as well as normal animals. The experimental animals were fed 500mg/kg/day of wheatgrass extract orally for a period of 12 weeks, after which the authors found a significant (p<0.05) decline in the serum TG, TAG, LDL and MDA levels of the animals in both the normal and hypercholesterolemic groups. Interestingly, the HDL cholesterol had increased in the normal group but decreased in the hypercholesterolemic group. In the present study too, the supplemental group, all of whom were hypercholesterolemics, saw a decline in the HDL levels.

Experiments on the glycemic and lipemic index of wheatgrass containing recipes (Iyer, Sharma, Dhruv and Mani 2009) have reported that incorporation of wheatgrass into recipes reduced the glycemic index and the TAG level response of the recipes as compared to without addition of wheatgrass.

The anti-inflammatoryeffect of wheatgrass can be attributed partly to the presence of beta sitosterol which has been found to exert protective effects against endothelial inflammation. Specifically, beta-sitosterol has been found to prevent inflammatory changes by suppressing vascular adhesion molecule 1 and intracellular adhesion molecule 1 expression in Tumor Necrosis Factor alpha (TNF-α)-stimulated human aortic endothelial cellsin addition to inhibiting binding of U937 cells to TNF-α-stimulated human aortic endothelial cells. It also attenuates the phosphorylation of nuclear factor-kappa B (Loizou 2010).

wheatgrass on oxidative stress can be attributed to its high antioxidant activity as reported by Kulkarni et al (2006). Specifically, the authors found that the ethanol extracts of wheatgrass were found to have higher phenolic and flavonoid content than the aqueous extracts. The authors also reported the antioxidant activity in terms of FRAP values, which were found to be 0.463 and 0.573 mmol of ascorbic acid and Trolox equivalents/100 g fresh wheatgrass for aqueous and ethanol extracts, respectively. These extracts were also found to inhibit significantly ascorbate-Fe2+ induced lipid peroxidation in rat liver mitochondria. The authors also reported the ORAC values of aqueous and ethanol extracts (39.9 and 48.2 respectively) being higher than those reported for many natural extracts or vegetables.

RATIONALE

The different level of saturation of risk factors in women, together with their interaction with female hormones, plays an important role in the development of cardiovascular disease; and given that middle women form a sizeable part of the Indian demography, the health expenses incurred towards chronic disease alleviation by this huge segment of the population would be a cause of grave concern for the stake holders. However, to sketch conclusive decisions on the interventions and the extent of coverage, comprehensive studies spanning the complete picture of the metabolic and cardio-vascular risk factors across a significant part of the Indian population is a pre-requisite.

But in this regard, most of the studies are on the western population and data in the regional context is lacking. Moreover, the review suggests that Indian studies even though documented, are scattered and do not provide an all-encompassing portrait of the situation.

In this context, a wide range of nutraceuticals and functional foods have been tried as has been reviewed, but discreetly designed trials on the Indian ethnic population groups are scarce and fail to provide any conclusive evidence. On the other hand, the benefits of the wonder herb of Ayurveda- Wheatgrass has been scientifically shown to possess a variety of vitamins, essential minerals, phytochemicals, antioxidants and other bioactive molecules which render wheatgrass to be a promising natural substance to be considered for reducing serum cholesterol and lipid peroxidation due to oxidative stress. Therefore, a scientifically designed trial in this regard is justified to separate myths from facts and to assess whether wheatgrass can be promoted as a functional food for the management of hyperlipidemia.

Hence a need was felt to undertake a set of studies which would address all these queries and the details of the research questions addressed therein are described in the subsequent section.

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