Worldwide, ageing is a phenomenon that grips every nation as the productive population will gradually age into geriatric population, a greater proportion of which will be women given that 55% of elderly in the world are women (UN 1988, WHO 2002). In India, middle-age population is increasing rapidly and forms the productive population. The latest 2011 census (Chandramouli 2011) estimates roughly half of the women (47.6%) in India are in the age group of 15-65 years. Demographic studies estimate that, in 1990, there were 467 million postmenopausal women in the world. Population projections based on these demographic studies predict that, by the year 2030, the number of postmenopausal women will increase to 1.2 billion. At this time, approx 47 million women will be entering menopause each year. Furthermore, it is estimated that women in developed countries will spend about 30 yr of their life in the postmenopausal state. This translates into increased public health spending on chronic diseases and eventually a drag on the Indian economy.
The health spending is highest, owing mainly to chronic diseases in middle-age and elderly population. This is evidently reflected in India's increasing spending on the health, the major part of which is in the private sector (4.5% of GDP as compared to 1.2% by the state in India's total public health spending of 5.2%). Half of this contributed by women, who unlike men, don't enjoy a smooth transition into the middle-age health risks, mainly on account of menopause. Moreover, there is evidence that Indian women may be comparatively worse off than men with regard to many of the risk factors for CHD, particularly post-menopausal women (Vlassof 2007, Silander et al 2008, Njelekela 2009, Ghosh et al 2010, Abbasi et al 2012).
MENOPAUSAL TRANSITION
Menopause signifies the cessation of ovarian function in women which marks the end of the reproductive life span in them. Clinically menopause is defined as absence of menstrual periods for atleast 12 consecutive months or more (Soules et al 2001). Although menopause is a discrete event in the reproductive lifespan, the stoppage of menstrual periods is not sudden; the event itself represents the culmination of an altered endocrinological situation, the origins of which usually precede the menopause by more than a decade. Based on this biological phenomenon of menopause, the reproductive classification of women is done into
Pre-Menopausal: Before the menopausal transition starts
Peri-Menopausal: the phase of transition from pre-menopause to menopause
Post-Menopausal: the period after menopause has occurred
Contrary to the popular belief, where the entire phase of transition into menopause is referred to as menopause; clinically menopause is considered as a single event that marks end of menstrual periods.
The mean age of occurrence of menopause is 51-52 years (Copeland 1993). But recent trends indicate a shift of this mean age a little earlier in life, and the factors disputed to be causative here are unhealthy dietary patterns and sedentary lifestyle and exposure to higher levels of environmental pollutants. But not only does any documentation exist on this shift in mean menopausal age in the Indian context, but also the role of diet and lifestyle has not been studied. Hence mapping needs to be done in Indian women and influence of diet and lifestyle needs to be reviewed.
It is worthwhile to note that while menopause is a natural phenomenon, it is listed as a 'disease' in International Classification of Diseases - 9 & 10, Disease Data Base, e-Medicine, and Medical Subject Headings. Menopause evidently alters the function of human body resulting in menopausal symptoms collectively called as 'menopausal syndrome' (Govil 2010).
Table 1 Clinical Reproductive Aging In Women
Reproductive Years
Menopausal Transition
Post-menopause
Average Age*
First Period:
9-15
16-30
31-42
Early transition
40s
Late transition
late 40s,
early 50s
Final Period: 51
50s
and beyond
Menstrual Cycles
Variable
Regular
Regular
Lengths of cycles
vary increasingly
2 or more
skipped periods
No period**
No periods
Signs and Symptoms
Fertility
progre-ssively
declines
Hot flashes
Irritability
Sleep
disturban-ces
Bone loss
begins.
Same
as previous
Vaginal dryness
Bone loss
Hot flashes
can persist
For a few
women, hot flashes
continue into their
60s and 70s
Source: American Society for Reproductive Medicine 2007
MENOPAUSAL SYNDROME
The biological effects of estrogen deficiency in females when the ovarian follicular stores decline, results in the a variety of symptoms with varying degrees of severity and discomfort. This syndrome is called menopausal syndrome. The main four classes of menopausal syndrome, according to the organ system being affected are classified into following four classes:
Vasomotor Symptoms
Somatic Symptoms
Psychological Symptoms
Urogenital Symptoms
Vasomotor Symptoms
Rghdhththth
Somatic Symptoms
Uhkkhulh
Psychological Symptoms
Ojljo;jo'jo'
Urogenital Symptoms
Large numbers of estrogen receptors are found in the vagina, vulva, urethra, and trigone of the bladder. Thus, atrophy of the genitourinary tract can occur as estrogen levels diminish.
After menopause, the vaginal walls thin and lose their elasticity. They also produce fewer secretions and lose much of their lubricating ability in response to sexual stimuli. The vulva becomes flattened and thin as a result of the loss of collagen, adipose tissue and the ability to retain water8. The urethra also becomes thinner and less efficient, with detrusor pressure at the urethral opening decreasing, both during and after voiding. Estrogen deficiency also leads to an increase in fibrosis of the bladder neck, reduced collagen in surrounding tissues, and a decrease in the number and diameter of the muscle fibers in the pelvic floor.
These changes increase a woman's risk of vaginal and urinary tract infection. Atrophic genitourinary tissues are also at increased risk of injury by trauma. Estrogen replacement therapy can significantly lessen these problems.
All of the changes to the genitourinary tract can result in dyspareunia, leading to a decreased interest in sexual intercourse. Fatigue and depression brought on by the vasomotor symptoms and sleep disturbances of menopause can exacerbate this lack of interest in coitus.
Decreased levels of endogenous testosterone, both in women who have undergone surgical menopause, as well as in those who experience natural menopause, may cause decreased libido9. Women who complain of lack of sex drive may be candidates for androgen replacement, as well as estrogen. In general, androgen levels do not decrease abruptly at menopause but decrease gradually as women age so that decreased libido may be a problem of older postmenopausal women (Dominiguez 2004).
Normal Female Reproductive Endocrinology: Sex Steroid Feedback Control Loop
Normal female reproductive endocrinology: sex steroid secretory feedback control loop
Fig Sex Steroid Secretory Feedback Control Loop
Endocrinology of Menopause
The onset of menopause is marked by irregularity in menstrual cycles and finally culminating in complete termination of menstruation. The endocrinologic changes of menopause result from interplay between declining ovarian function and reciprocal changes in circulating gonadotropins. For five to seven years before the onset of the last menstrual period, ovarian function begins to diminish. Thus one of the main ovarian hormones, Estrogen begins to diminish. This affects the pituitary feedback mechanisms and manifests as increased levels of Follicle Stimulating Hormone (FSH), secreted by the anterior pituitary for stimulating the ovaries to increase the production of estrogen.
Both steroids and protein hormones from the ovary control pituitary production and secretion of LH and FSH. The principal ovarian steroid hormones are estradiol (predominant in the follicular phase) and progesterone (predominant in the luteal phase). These steroids regulate gona dotropin production and release via feedback loops of the hypothalamic-pituitary-ovarian axis. In addition, several peptide hormones (inhibin, activin, and follistatin) produced by granulosa cells influence FSH synthesis and secretion.
Concurrently, the production Inhibin B, which is a hormone secreted by the small antral follicles and is a major regulator of FSH, declines due to age-related decline in the number of follicles in the ovary, which in turn, leads to further increase in FSH (Warren and Dominguez, 2004). Women older than the age of 45 exhibited menstrual irregularity when the average number of primordial follicles per ovary decreased to approximately 100 (Burger et al 2008).
The role of inhibin in the regulation of FSH secretion has received considerable attention given the dynamic changes in serum concentrations that occur over the menstrual cycle. There are two types of inhibin, each consisting of the same aa-subunit combined with a either bA- or bB-subunit to form inhibin-A and inhibin-B, respectively. These dimeric inhibins show different patterns of secretion during the menstrual cycle. Levels of inhibin-A are low during the follicular phase, rise with ovulation, and peak during the luteal phase (76). In contrast, inhibin-B levels are highest during the midfollicular phase, decline at midcycle, and display a transient rise shortly after the LH surge (77)
One of the most consistent endocrinologic changes associated with onset of the perimenopause is the monotropic rise in FSH (7882). It has been hypothesized that this change in FSH may result from diminished function of the granulosa cell compartment of the ovary, manifested by decreased production of estradiol, inhibin, and/or insulin-like growth factors (IGFs)
Early studies showed that elevations in FSH are often accompanied by decreases in circulating levels of estradiol (79,83,84) and inhibin (8386). Other studies of the perimenopausal transition have shown no significant change in estradiol levels (80,81) or elevated estrogen levels (8789). These apparent conflicts in the literature may reflect differences in the timing of the sample collections over the perimenopausal transition. Perhaps, initially, the increase in FSH compensates for decreasing ovarian function and results in increased estradiol levels. Then, as the ovary continues to age in the latter part of the perimenopausal transition, a decline in estradiol occurs. Declining inhibin rather than estradiol production by the granulosa cells during the early phase of the perimenopause may be important in initiating the monotropic rise in FSH (9091). Whereas some studies using a polyclonal antibody to the a-subunit have failed to show a change in serum inhibin concentrations associated with the monotropic rise in FSH (87,92,93), decreased secretion of inhibin-B has been shown to be associated with this elevation in FSH (94). Thus, decreased inhibin-B may reflect diminished function of the granulosa cells of older women and play a role in the regulation of FSH during the perimenopause (95).
These changes disrupt the feedback control loop of estrogen release and throw the whole hypothalamo-pituitary-ovarian axis into chaos. As a result a typical pattern of plasma hormonal levels (shown in Fig) results in the phases surrounding menopause. In this pattern, there are two estrogen level peaks following FSH peaks and a progesterone peak following an LH peak in premenopausal phase. In the peri menopausal phase, the sex hormone production starts declining resulting in highly erratic increases in releasing hormones. Finally after the menopausal transition is complete, the ovarian sex hormone production drops to the minimum with releasing hormone levels remaining elevated throughout.
In summary, the earliest endocrinologic evidence of diminished ovarian reserve may be diminished inhibin-B secretion and the monotropic rise in FSH. This may occur in the presence of elevated circulating levels of estradiol.
DIMINISHED OVARIAN RESERVE
Peri Menopause
The locus of reproductive aging is the ovary. It is here that the seeds of menopause are sown, because the ovary contains a finite number of irreplaceable primordial follicles. The perimenopausal years are marked by their accelerated attrition. As the number of ollicles dwindles, elaboration of ovarian hormones appears to change somewhat unpredictably. The menstrual regularity a woman experiences during the perimenopausal years appears to be more related to her remaining primordial follicle number than to her age (40). As the number diminishes, irregular bleeding can occur after an estradiol peak without subsequent ovulation or corpus luteum formation. Both normal (36,41) and inadequate (38,42) corpus luteum secretion of progesterone have been described in perimenopausal women.
Coordinately, early follicular phase estradiol concentrations are elevated in perimenopausal women compared with midreproductive-aged women(27,32,38,45,46). In two small studies of women aged 43 and older who were still cycling, ovulatory cycles with high estrogen production were observed (38,46), suggesting that this accelerated folliculogenesis could be exuberant throughout . In other words, the ovary, less responsive to FSH, requires greater circulating quantities of FSH to initiate folliculogenesis. Once started, FSH induces an ''overshoot" of estradiol and consequently, hyperestrogenemia occurs. These elevations in estrogen may be a feature of the early perimenopause, with reduced estrogen accounting for the menstrual cycles immediately preceding menopause. It is clinically important to understand how commonly diminished progesterone secretion might be coupled with hyperestrogenic cycles, since this combination predisposes women to menorrhagia, endometrial hyperplasia, dysfunctional uterine bleeding, and even endometrial cancer.
Glycoprotein hormones elaborated by the granulosa cell include inhibin, a disulfide linked heterodimer, which has been shown to decrease over the perimenopausal transition (34,39). A decrease in inhibin secretion by the granulosa cells begins at approximately age 35, but accelerates dramatically after age 40. The decline in inhibin, which probably reflects both lesser follicular competence and a smaller ovarian follicular pool, is believed to facilitate the early follicular phase rise in FSH. Activin, a homodimer of the inhibin b-subunit, may be increased locally in the perimenopausal ovary, since inhibin a-subunit is declining at this time of life (34). This increase in activin may further increase circulating FSH, and, at least in an animal model, has been shown to lead to hyperestrogenic superovulation (50).
Thus, the early perimenopause is heralded by the appearance of elevated FSH, possible elevations in estrogen, and decreased progesterone secretion. The hormonal milieu is one of relatively unopposed estrogen, and this may promote the growth of uterine leiomyomata and a variety of disconcerting bleeding problems. The perimenopausal reproductive hormonal environment should not be regarded as a simple waning of ovarian function over time. It is a waxing and waning process, at times more like a "roller coaster" in its hormonal dynamics.
Menopause
At the time of menopause, the ovary is nearly devoid of primordial follicles (51). Granulosa cell estrogen production is essentially nonexistent. The circulating level of estrogen in women shows a very steep decline over the first 12 mo after the menopause, with only a very slight further decline in the years thereafter (52,53). The daily production rate of estrogen falls nearly eightfold to a level of approx 48 mg per 24 h. Essentially, all estrogen in the postmenopausal woman is derived from the peripheral conversion of androstenedione. Indeed, postmenopausal women who have undergone bilateral oophorectomies for endometrial cancer show no significant reduction in their circulating levels or urinary excretion rates of estrogen (5456).
Glucocorticoid suppression, however, dramatically reduces the circulating level of estrogen(54,57), whereas adrenalectomy effectively eliminates measurable estrogens from the urine (55). The circulating level of estrone in postmenopausal women is approx 3070 pg/mL. The circulating level of estradiol is even lower, approx 1020 pg/mL, as most is derived from the peripheral conversion of estrone (53,58,59). Estrone sulfate is an inactive metabolite of both estradiol and estrone, which diminishes in a similar manner postmenopausally. However, it still is present in higher concentrations than its precursors in both plasma and breast tumor tissue. It may have significant biological effects as culture studies with rat mammary tumor cell lines show nearly complete desulfation of the hormone and tumor colony proliferation (60). Sporadic and transient increases in estradiol concentrations, neither accompanied nor followed by elevations in progesterone, have been noted in some postmenopausal women (61). Such instances may represent residual follicular activity without subsequent ovulation, or perhaps are associated with stromal hyperplasia.
Ovarian stromas possess a limited capacity to aromatize androgens and therefore to more directly contribute to the circulating pool of estrogen. Immunohistochemical examination of ovarian stromal cells has also recently demonstrated the presence of aromatase cytochrome P-450 in both pre and postmenopausal ovaries (68). Whatever ability to aromatize androgens the postmenopausal ovary may possess in vivo, it is generally agreed to be at most quite limited. This may be because of a disproportionately lower concentration of FSH as compared to LH receptors in the ovarian stromal cells.
Androgen Production
As women traverse the menopause, ovarian androgen secretion declines (52,69). Midcycle testosterone and androstenedione have been reported to be decreased at midcycle in women in their mid-40s who are still having regular menstrual periods, when compared to younger, midreproductive-aged women (70). This aside, a solid foundation of evidence exists that demonstrates the postmenopausal ovary to remain a highly functional androgen-secreting organ. Histologic examination reveals the stromal cell of the ovarian cortex and the hilar cell of the ovarian medulla to be responsible for this production
EFFECTS OF MENOPAUSAL ENDOCRINOLOGICAL CHANGES ON BODY COMPOSITION, CHRONIC DISEASE PHYSIOLOGY AND METABOLISM
Estrogen receptors are present in various organ systems in the body, hence depletion in estrogen, exerts an effect of deficiency on these organ systems, one among these being the cardiovascular system.
Effects on Body Composition
A number of studies have been reported the association of menopausal transition and changes in body composition, especially increase in the visceral fat depot in women (Ley et al 1992, Hunter et al 1996, Tremollieres et al 1996, Reubinoff et al 1995, Lovejoy et al 2008). Franklin et al (2009) followed up 8 pre menopausal women for 8 years till they were one complete year into their menopause and studied the changes in total body fat and distribution
Effects of Estrogen and Estrogen Withdrawal on the Physiology of the Heart and Vasculature
The addition of estrogen has been shown to increase cardiac output, arterial compliance, and myocardial perfusion, and to decrease vascular resistance and systolic and diastolic blood pressure both in animals and humans. The effect of the physiologic removal of estrogen with menopause on cardiovascular function is less clear.
Changes in Blood Flow
The endothelium plays a critical role in the control of blood flow in the interaction between the blood and the vessel wall. Endothelial function has been assessed in patients by measuring coronary hemodynamic response to intracoronary administration of an endothelium dependent vasodilator, acetylcholine. Coronaries with normally functioning endothelium exhibit acetylcholine-induced dilation, manifested by an increased epicardial cross-sectional area and coronary flow augmentation. In patients with atherosclerosis or dysfunctional endothelium, paradoxical acetylcholine-induced constriction is manifested by decreases both in area and blood flow. Of note, acetylcholine-induced changes in coronary tone mimic those to common vasomotor stimuli, such as exercise and mental stress and, thus, are useful in experimental settings. Endothelial dysfunction is increasingly recognized as an important factor in the progression of cardiovascular disease. Numerous studies suggest that estrogen has a beneficial effect on endothelial dysfunction and, thus, declining estrogen levels with menopause and the subsequent negative effect on vascular tone, could be an important mechanism by which atherosclerosis occurs in postmenopausal women. The clinical evidence and proposed mechanisms are summarized below.
Effects on Vasculature
Most of the recent literature has focused on the effects (acute and chronic) of estrogen administration to postmenopausal women with atherosclerosis and impaired vascular tone. A few cross-sectional studies have looked at the direct effect of menopause (and, thus, estrogen withdrawal) on vascular tone. A group of investigators used high resolution ultrasound to evaluate endothelial responsiveness in the brachial artery (which has been shown to be an effective proxy for coronary endothelial function (13). in a large series of males and females) (11). Flow-mediated dilation was preserved in young male subjects and then declined after 40 yr of age. In women, however, flow mediated dilation was maintained until the early 50s, and then declined significantly more than it did in men. Another recent study looked at both normotensive and hypertensive males and females and found that age-related endothelial dysfunction is attenuated in premenopausal women both with and without hypertension as compared to males. This gender difference was not seen postmenopausally (14). The same authors who studied changes in forearm blood flow
used brachial artery strain gauge plethysmography to measure the effect of surgical menopause on vascular tone in a small series of women who were scheduled to have TAH/BSO for uterine leiomyoma. In association with dramatic drops in estrogen levels these women had a significant reduction in acetylcholine-induced vasodilation compared to their presurgical baseline. These changes were significantly attenuated in a small subset of the women who received estrogen replacement over the next three months (15).
There are data that both short- and long-term estrogen administration improves endothelial cell-mediated vasodilation in ovariectomized monkeys fed an atherogenic diet (15,16,18). Recent studies looking at the effects of estrogen administration on vascular tone in postmenopausal women are summarized in Table 2. Most of these studies have looked at the acute effect of estrogen on vascular reactivity. As seen in Table 2, earlier studies used cardiac catheterization to measure coronary flow resistance in cross-sectional areas before and after intravenous estrogen. Later studies used brachial strain gauge plethysmography and brachial artery high-resolution ultrasound. There is limited data on the effects of long-term estrogen administration and coronary endothelial cell function. One study, in ovariectomized monkeys treated with hormonal replacement for 26 mo, has shown a beneficial effect (17). A study by Lieberman (22), treated 13 postmenopausal women with hormone replacement therapy in a double-blind placebo controlled crossover trial. Measurements of flow-mediated vasodilation of the brachial artery taken at the end of each 9-wk treatment suggested statistically significant changes in flow-mediated vasodilation in postmenopausal women on short-term hormone replacement therapy. In contrast, Gilligan (24) found no improvement after 3 wk of hormone replacement therapy in contrast to the effect of acute estrogen administration on flow mediated dilation using the same method. The recent study by McCrohon, which was a cross-sectional study comparing postmenopausal women who had taken HRT with age-matched controls (who had never taken HRT), demonstrated statistically significantly greater flow mediated dilation in women taking HRT, as measured by brachial artery high-resolution ultrasound (26).
In summary, clinical studies suggest a role for acute estrogen in the improvement of endothelial-dependent flow-mediated vasodilation. The data for short-term or chronic hormone replacement therapy is less clear. There are a number of possible reasons for these differences. First, the plasma level of estradiol achieved by acute infusion, when measured in studies, was 34 times higher than what would be achieved by usual doses of hormone replacement therapy. It is also possible that chronic estrogen administration acts through different cellular mechanisms in regulating vascular tone. Finally, studies to date have been limited to small sample sizes, suggesting the possibility of a beta error (i.e., inability to detect a small benefit in vasomotor responsiveness in patients on chronic hormone replacement therapy).
Endothelium Dependent Vasodilation
The endothelium consists of a monolayer of cells that lines the intimal surface of the entire cardiovascular system. It plays a major role in regulating vascular tone through the release of dilator and constrictor substances that act upon vascular smooth muscle. There is accumulating evidence that impairment of endothelium-mediated vasodilation is an important early feature in the development of vascular disease not only in patients with known atherosclerosis but also with patients with hypertension, hypercholesterolemia, smoking, and diabetes (3237).
Nitric Oxide
Endothelium dependent vasodilators, such as acetylcholine stimulate the endothelium to produce endothelial-derived relaxing factor (EDRF), which is nitric oxide (NO). Nitric oxide is released by normal vascular endothelium in response to many types of clinical and physical stimuli, including neurotransmitters (acetylcholine), catecholamines, platelet products (serotonin), shear stress and changes in oxygen tension. NO causes vasodilation in endothelium intact coronary arteries and is a product of the conversion of L-arginine by nitric oxide synthetase (NOS) to NO and citrulline. NO is released in response to many factors, including acetylcholine, causing a subsequent relaxation of the blood vessel. In arteries damaged by atherosclerosis, however, acetylcholine causes constriction suggesting that atheroma impairs endothelium mediated dilation of the coronary arteries. Patients with central hypertension also have impaired endothelium dependent vasodilation. At least one study has demonstrated that abnormal endothelial function of patients with central hypertension is related to a defect in the endothelium-derived nitric oxide system, because of reduced synthesis, release, or diffusion of nitric oxide to vascular smooth muscle (38).
NO has several actions that are cardioprotective including vasodilation, inhibition of platelet adhesion and aggregation, and inhibition of smooth muscle cell proliferation and the amount of available NOS in a cell. NO has also been observed to slow the development of atheroma by inhibiting smooth cell proliferation or stimulating proliferation of endothelial cells. Estrogen is also a potent antioxidant of lipids and oxidized lipids inhibit NO. Estrogen may, therefore, protect the vascular tone by enhancing and/or prolonging the half-life of released NO. The time course for this effect is unknown and effects may only be seen with long-term estrogen therapy. In one study of HRT in postmenopausal women, researchers measured NO2 and NO3 levels as markers for NOS synthase activity and found an increase in women who were on estrogen alone (40). One study in guinea pigs has suggested that long-term administration of estrogen up-regulates the transcription of nitric oxide synthase. A recent study in humans has demonstrated variations in expired NO production with cyclical hormone changes in premenopausal women. NO levels peak at the middle of the menstrual cycle suggesting an influence of hormones on the synthesis and release of NO in humans (41).
Calcium Antagonism
Vascular smooth muscle (VSM) contraction is enhanced by intravascular calcium. Substances that block the flow of calcium into cells cause VSM relaxation and decreased vascular tone. It has been hypothesized, based on animal models, that some of the cardiovascular benefit of estrogen replacement therapy may be because of a calcium antagonistic effect of estrogen (43). These properties have been demonstrated in several animal models. 17-b Estradiol was shown to have a negative inotropic effect on single-isolated guinea pig ventricular myocytes by inhibiting inward calcium currents and so reducing intracellular free calcium (42).
Prostaglandins
Prostacyclin is a prostaglandin produced by endothelial cells. Its synthesis is thought to be coupled to NO release. It has been shown to induce vasodilation and inhibition of platelet activation in animal models. Evidence in humans is scant, but there is an indication that estrogen may effect coagulation and vasodilatation by its effects on prostacyclin (39).
Inhibition of Constrictor Factors
Animal studies suggest that estrogen inhibits the release of or response to vascular constrictor factors. Vasoconstrictors include endothelin and fibronectin. There is a correlation between high endothelin levels and the development of atherosclerosis in humans (44). One study demonstrated that plasma endothelin levels tend to be higher in men than women and lower still in pregnant women (45). As a corollary, the same authors demonstrated in transsexuals that sex hormones may modulate endothelin levels, with male hormones increasing and female hormones decreasing the level. The effect of declining levels of estrogen with menopause on vascular constrictor factors is still unclear.
Estrogen also inhibits angiotensin II-induced constrictor effects in animal studies suggesting an inhibitory effect on the renin-angiotensin system (39). In males elevated activity of serum angiotensin-converting-enzyme (ACE) may be associated with an increased risk of developing CAD. To date, there are no studies looking at ACE levels in women pre- and postmenopausally and correlating them with increased risk of developing CAD. In one of postmenopausal women treated with 6 mo of hormone replacement therapy, ACE-activity was reduced by 20% in 28 treated women as compared with 16 untreated controls (46).
Effects on Vasoactive Neurotransmitters
Epinephrine and norepinephrine are released from sympathetic and parasympathetic nerve endings in the arterial wall and, thus, can cause vasoconstriction and vasodilation, playing an important role in the maintenance of vascular tone. Estrogens and progestins are thought to influence the release of these neurotransmitters by several mechanisms (47). Of note, vasomotor instability (VMI) the hallmark of estrogen deficiency, occurs with rapid fluctuations in serum epinephrine and norepinephrine concentrations. Medications that decrease central noradrenergic activity, such as clonidine, have been shown to successfully treat hot flashes. The decline of estrogen levels that is seen with menopause is also associated with a relative increase in catecholamine release associated with physical and mental stress (48).
Effects on Vascular Wall Composition
Animal studies have shown that vascular smooth muscle hyperplasia and collagen biosynthesis are reduced by estrogen administration (49). 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 effect 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. 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 redcution in endogenous hormones. This is certainly supported by the beneficial effect of postmenopausal hormone therapy on lipoprotein metabolism in postmenopasusal 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-ï¢ estradiol appears to inhibit LDL oxidation and reduce cholesterol ester formation (68). In one study, 17-ï¢ 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).
Fig Changes in Hormone Level Patterns Over Six Months
http://www.nia.nih.gov/NR/rdonlyres/45F306F1-3736-4646-94B9-663B034DEAE2/9524/01_chart1.gifhttp://www.nia.nih.gov/NR/rdonlyres/45F306F1-3736-4646-94B9-663B034DEAE2/9524/01_chart1.gif
http://www.nia.nih.gov/NR/rdonlyres/45F306F1-3736-4646-94B9-663B034DEAE2/9524/01_chart1.gif
Source: Harvard Women's Health Watch 1999
Fig Estrogen Levels From Puberty to Menopause
Source:
Menopausal Syndrome
The above discussed changes in hormone levels during menopausal transition result in a variety of symptoms which cause varying degrees of discomfort and is collectively known as the Menopausal Syndrome. Menopausal symptoms affect the areas where the lack of estrogen effect is felt due to menopausal transition. These areas are the
temperature regulating center of the hypothalamus which causes hot flashes and night sweats
vascular endothelium, which increases risk of CVD
bone which undergoes more resorption
vaginal muscles, which atrophy and become thin
urinary bladder muscles, which lose a little bit of tone resulting in incontinence
adipose tissue beneath the skin which atrophies resulting in rougher and looser skin
The symptoms (rapid effects) which are commonly seen in women experiencing menopause and which have been established to be upshots of menopausal transition are vasomotor symptoms. These include hot flashes and night sweats. The prevalence of vasomotor symptoms runs as high as 45.6% in African American women, 35.4% in Hispanic women, 31.2% in white women, 20.5% in Chinese women and 17.8% in Japanese women6. In a study done in underprivileged middle aged women (Chauhan and Nair 2006) in Vadodara district, the prevalence of vasomotor symptoms was reported to be 38% moderate hot flashes and 19% hot flashes of severe nature. Other symptoms reported by them were backache (71%), swelling in hands/legs (27% moderate, 26% severe)
MENOPAUSAL TRANSITION AND CHRONIC DISEASE PHYSIOLOGY
The effects estrogen has on cardiovascular system can be viewed as rapid effect which follows the non-genetic route and includes estrogen mediated vasodilatation. Then there are slow effects which are genetic in nature and include production of vasodilative substances, beneficial effects in lipid profile and resistance to atherosclerosis. Thus low estrogen levels during menopause, has detrimental effects on the vasculature, lipid profile, coagulation and fibrinolytic systems (Wood and Cox 2000).
Fig: Cascade of Metabolic Events due to Estrogen Deficiency
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WHEATGRASS - THE WONDER HERB OF AYURVEDA
The antiprolifrative and anti tumor effect of wheat leaf ribonuclease was tested in vitro on human ML-2 cell line and in vivo on athymic nude mice bearing human melanoma tumors. The antiproliferative activity of this plant ribinuclease was negligible in comperision with bovine seminal ribonuclease. In the experiments in vivo, a significant decrease of tumor size however was observed in the mice treated with wheat leaf ribonuclease compared with the control Rnase and polyethyleneglycol [45 (Adom KK, Sorrells ME, Liu RH. Phytochemical profiles and antioxidant activity of wheat varities. J Agric Food Chem 2003; 51(26): 7225-34. ) Vol 1:4 (2011) IJPI'S Journal of Pharmacognosy and Herbal Formulations Shankul Kumar et al Page 101 ]
The antioxidant activity of wheatgrass was estimated at different levels. The methods employed include FRAP, ABTS, and DPPH assays. Aqueous and ethanol extracts of wheatgrass grown under different conditions over a period of 6, 7, 8, 10 and 15 days were used. Lipid peroxidation and oxygen radical absorbance capacity (ORAC) were determined and utilized to check the potency of a few selected extracts. . Different conditions used for growth were (1) tap water, (2) tap water with nutrients, (3) soil and tap water, and (4) soil with nutrients. The ethanol extracts were found to have a higher phenolic and flavonoid content than the aqueous extracts. The highest FRAP values occurred on day 15 of growth under condition 4, the values being 0.463 and 0.573 mmol of ascorbic acid and Trolox equivalents/100 g fresh wheatgrass for aqueous and ethanol extracts, respectively [52 (Siener R, Honow R, Voss S, Seidler A, Hesse A. Oxalate content of cereals and cereal products. J Agric Food Chem. 2006 Apr 19; 54(8): 3008-11. )]
Julian EA, Jhonson G, Jhonson DK, Donnelly BJ. The glycoflavonoid pigmens of wheat,Triticum aestivum, leaves. Phytochemistry 1971; 10 (12): 3185-93.
Kulkarni SD, Tilak JC, Acharya R, Rajurkar NS, Devasagayam TP, Reddy AV. Evaluation of the antioxidant activity of wheat grass (Triticum aestivum L.) as a function of growth under different conditions. Phytother Res. 2006; 20(3): 218-27 .
Skvor J, Lipovova P, Pouckova P, Soucek J, Slavik K, Matousek J. effect of wheat leaf ribonuclease on tumor cells and tissue. Anticancer drugs 2006; 17(7): 815-23.
Falcioni G, Fedeli D, Tiano L, Mancinelli L, Marsili V, Gianfranceschi G. Antioxidant activity of wheat sprouts extracts invitro:inhibition of DNA oxidative damage. Journal of Food Science2002; 67(8): 2918-22.
Kulkarni SD, Tilak JC, Acharya R, Rajurkar NS, Devasagayam TP, Reddy AV. Evaluation of the antioxidant activity of wheat grass (Triticum aestivum L.) as a function of growth under different conditions.Phytother Res. 2006; 20(3): 218-27.
Kyrychenko OV, Tyshchenko OM. Effect of exogenous specific lectin on lectin activity in the wheat seedlings and leaves. Ukr Biokhim Zh. 2005; 77(4): 133-7.
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.
