REVIEW: THE STUDY OF EFFECTOFBOTANICALS AND NUTRACEUTICALS IN FEMALE SEXUAL DYSFUNCTIONAND IN MENOPAUSE

Ganesh Kamath, Supriya Yadav, Bharat Acharaya and Rashmi Mungekar Vital Neutraceuticals Pvt.Ltd., Mahararshtra, India. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 20 January 2020 Final Accepted: 22 February 2020 Published: March 2020


ISSN: 2320-5407
Int. J. Adv. Res. 8(03), 803-816 806 Urinary incontinence Psychosocial Factors: Several of the following psychosocial factors that are common during midlife are associated with sexual dysfunction: 1. Mood symptoms, such as depression and anxiety 2. Life stressors, such as career and family demands 3. A history of trauma, particularly sexual trauma The development of depression and anxiety symptoms during the menopausal transition is common.Mood disorders and sexual dysfunction are highly comorbid,with 25% to 75% of depressed women reporting sexual problemseven when controlling for other factors. [14][15][16] It is important for providers to screen women with sexual complaints for depression and anxiety symptoms and recognize that not all women with sexual dysfunction have a mood disorder. Everyday life stressors also have a negative impact. [16][17][18] Midlife women may be caring for children of their own, may have adult children return home, and/or be caring for aging parents. 18 Job-related stress and financial concerns are also common. 18 Providers should be attuned to the effects of life stressors and work with women to develop stress reduction strategies, such as mindfulness meditation.

Interpersonal Factors:
Most midlife women are sexually active with a partner,and partner-associated issues can affect the woman's sexual function, as follows: 1. Positive relationship aspects: higher relationship satisfaction and intimacy are associated with better sexual function, 19,20 and the ability to openly communicate with one's partner is of key importance. 18 2. Loss or gain of a partner: Many women experience the loss of a partner (to death, divorce, or separation) at midlife, and some gain a new partner, both of which can affect sexual function.Gain of a new partner is associated with increased desire, arousal, and emotional satisfaction with sex. 15 3. Issues affecting aging partners: Partners may develop medical problems, medications, or sexual dysfunction that can affect the woman's sexual function. In particular, erectile dysfunction in male partners is associated with decreased sexual function and satisfaction in female partners. 18

Part I: Medicinal Plants as Alternative Treatments for Female Sexual Dysfunction:
Female sexual dysfunctions (FSD) are understood as multifactorial and multidimensionalhealth issues that are associated with physical andemotional conditions. 21 In this regard, the use of medicinal plants for several diseases has increased in Western cultures 22 and in other parts of the world. A Japanese study suggested that complementary and alternative medicines are used more frequently by females than males 23 . Most women report thepreference for herbal products based on the idea that these products are natural, safe, and more congruent with their values and lifestyles.
This review focuses on the use of medicinal plants for the treatment of FSD to provide additional evidence of possible therapeutic approaches for women with sexual problems. The medicinal plants described below have clinical and popular use and have been widely used around the world in many different cultures and in several medical approaches. More specifically, we have highlighted the medicinal plants that are commonly used for FSD, mainly in climacteric women. Theplants presented in this review, such as Tribulus terrestries, Mucunapruriens, L-Arginine, Grape Seed Extract, have effects on the female reproductivesystem, and their use in FSD studies has been proposed due to their mechanisms of action.

Tribulus terrestries:
Prescribing Tribulus extract for women can increase desire score in women who suffer from loss of sex desire. However, according to our knowledge there has not been any similar research on the impact of Tribulus extract in improving women's sex desire in childbearing age. The effect of testosterone in improving desire in menopausal women has been confirmed by studies that have looked at women's sex drive and how to boost it. The role of conjugated testosterone in treating lack of sex drive has been emphasized. Currently testosterone is the only approved drug for treatment of HSDD inmenopausal women, particularly for those have surgicallyinduced menopause. However, Tribulus is the only drug which not only improves the sexual desirein women but also it does not have any unexpected side effects in patients. 24 Tribulus terrestris have a potential double effect, improving sexual desire through an increase in free testosterone and also improving arousal by means of a vaginal vasodilating effect. 25 T. terrestrisis often used in the treatment of infertility, decreased libido, and erectile dysfunction. It is also used among athletes to increase muscle resistance and improve performance in sports, although scientific evidence to support this effect is lacking. 21 The active components of T. terrestrisinclude the steroidal glycoside saponins furostanol and spirostanol, which are found in the leaves of the plant. 26 Protodioscin is a chemical substance derived from the T. terrestrisplant that has been confirmed to increase sexual desire and improve erections by means of conversion of protodioscin to (Dehydroepiandrosterone)DHEA. 21,27 In animal studies, increased testosterone levels along with increased dehydrotestosterone and DHEA are suggestive of aphrodisiac activity. 21,26,[28][29][30] The co-occurrence of enhanced female sexual function and increased DHEA levels is suggestive of physiological alterations underlying clinical improvement following treatment. The study of Nunes et al strongly support the safety and effectiveness of T. terrestrisextract in the treatment of female sexual dysfunction 31 Tribulus terrestris, puncture vine has long been used in traditional medicine to treat impotency and improve sexual functions. The study of Esfandiariet al,investigated the effect of Tribulus trestris extract on ovarian activity of immature wistar rat. Results showed that number of corpus luteum and diameter of theca interna increased in treatment group as compared with control group. Number of secondary and graafian follicles after 14 days treatment was higher than control and 7 days treatment. The results indicated that Tribulus terrestris induces corpus luteum formation and growth and therefore beginning of puberty with its LH-like activity. In addition, increased in corpus luteum diameter may relate to increased progesterone production. 32 Opioids can exert adverse effects on the body. Morphine, an opioid drug,reduces hormone levels and fertility, and causes sexual activity disorders. Tribulus terrestris(TT) is a traditional herbal medicine used to enhance sexual activities. The studyinvestigated the possible role of TT on sex hormones and gonadotropins with the intent toshow its usefulness in treating fertility disorders in opioid users. Overall, except forfollicle-stimulating hormone (FSH), morphine reduced most of the gonadotropins andsexual hormones. Whereas TT caused a considerable increase (p<0.05) in the hormonesin the treated addicted group, there was only a slight increase in the treated control group.Oral consumption of TT could markedly antagonize the reduction of sexhormones and gonadotropins (except for FSH) due to morphine addiction. 33 Aphrodisiacs are substances, foods, drinks, and behaviours that throughout history have had reputations for making sex more attainable and pleasurable. It has been long believed that TT possesses aphrodisiac properties purportedly attributed to its ability to influence the levels or mimic function of sex hormones. This optimistic and hopeful notion was initially developed on epistemological assumptions and further nurtured andfostered by the persuasive but, perhaps, disquieting attraction to the idea of -natural‖ versus -artificial‖. The popularity of medicinal products from TT is expanding at aremarkable pace among consumers who are attempting to enhance their sexual health. 34 Using three double-blind randomized controlled trials, this selective systematic analysis reviewed the safety and efficacy of Tribulus terrestris in improving the sexual desire in women with HSDD older than 18 years of age. Exclusion criteria were exhaustive and included both medical and psychological conditions, medications, and other sexual dysfunctions in addition to HSDD. All three trials using the FSFI and QS-F questionnaires showed that in these women with HSDD, taking Tribulus terrestris was associated with a statistically significant increase in sexual desire. 9 Tribulus terrestris safely and effectively improve sexual desire in women with HSDD. No serious orlife-threatening adverse reactions were reported.

Mucunapruriens:
All parts of M. prurienspossess valuable medicinal properties in traditional system of medicine in India and West Africa used as a uterine stimulant and aphrodisiac. The seeds have been reported to be antidiabetic, antifungal, antioxidant activity, hypotensive, hypocholesterolemic, aphrodisiac, immunomodulator, cough, debility (physical weakness due to illness), dysentery, dysmenorrhea, fertility, impotency, night dreams, sterility, tuberculosis, uterine stimulant. The seeds are astringent, laxative, anthelmintic, aphrodisiac and tonic. 35 The seeds of M. prurienshave nonprotein amino acid (3-(3, 4-dihydroxyphenyl)-1-alanine) L-dopa for the first time in 1937 as a major constituent and mainly in seeds. L-DOPA is present at about 1% by fresh weight in leaves and roots of M. pruriens. The fully matured M. pruriensseeds ranges 3.6 to 4.2%, pod-pericarp 0.14 to 0.22%, leaves 0.17 to 0.35%, stems 0.19 to 0.31% and roots 0.12 to 0-.16% and the highest amount of L-DOPA was found in half mature seeds. The unusual non protein amino acid and a direct precursor to the neurotransmitter dopamine, is an important brain chemical involved in mood, sexuality and movement. 36 The increase in the number of oocytes released at ovulation with the use of M. pruriens has also been reported in previous report by using the seed. It can be attributed to the presence of L-Dopa in the leave. Increase in dopamine, a metabolite of L-Dopa has been reported to stimulate gonadotrophin releasing hormone (GnRH), which in turn activates the secretion of follicle stimulating hormone (FSH), resulting in the increase in oocyte number. This increase in oocyte number is thus evident as the corresponding increase in the reproductive outcome. 37 Sexual behaviour tests showed that the ethanolic seed extract of M. pruriens possesses significant sexual function enhancing activity. 38 Significant uterine weight gain was observed in moist and dry condition which might be due to the presence of estrogenic activity in the plant M. pruriens which was administered in the ethanolic extract form to the mice. Thus, M. pruriens possess a good estrogenic activity. 39 It can therefore be said that the use of M. pruriensincreases fertility and can be used as a potent medication in female sexual dysfunction.

Grape Seed Extract:
Oxidative stress is an important inducement in ovarian aging which results in fecundity decline in human and diverse animals. As a potent antioxidant, grape seed proanthocyanidin extract (GSPE) was investigated to ameliorate chicken ovarian aging. Firstly, ovarian antioxidant capacity of hens at different ages (90, 150, 280, and 580 days old) was compared to elucidate its age-related changes. Subsequently, a D-gal-induced (2.5 mg/mL) aging ovarian model was established and the cultured ovarian tissues were treated with GSPE at 5 μg/mL for 72 h to evaluate the putative attenuating effects of GSPE on ovarian aging. Meanwhile, ovaries of D280 (young) and D580 (old) were treated with GSPE for 72 h in culture to verify the protective effects of GSPE on natural aging ovary. The results showed that GSPE could rescue the antioxidant capacity decline by increasing the antioxidase activities and their gene expression in either D-gal-induced or natural aging ovaries. 42 Moreover, GSPE could maintain the homeostasis between cell proliferation and apoptosis in the D-gal-induced and natural aging ovaries, as well as alleviate D-gal-induced nucleus chromatin condensation in the ovarian granulosa cells. In conclusion, GSPE treatment can effectively prevent the ovarian aging process in hens by reducing oxidative stress 42 which will help to maintain the sexual health of females at later age of their life.
Supplementation of polyphenols can serve as an alternative method to stimulate estrogen secretion. Grape seeds contain various polyphenols at a concentration of approximately 2178.8 mg/g gallic acid equivalent (GAE), which is considerably higher than that observed in grape skin (374.6 mg/g GAE) and grape leaves (351.6 mg/g GAE). Grape seed extract (GSE) supplementation is known to induce estrogen synthesis by normalizing estrogen receptor deficiency. 43 Grape seed polyphenols also have several beneficial health effects, most notably, anticancerand vasorelaxant effects. 44 One of the most abundant ingredients of grapes are phenolic compounds which are present in large amounts. Grape seed is one of the richest sources of polyphenols, which exhibit antioxidant, free radical scavenging properties, and lipid lowering effects. The most common polyphenols of grape seeds are procyanidins ranging in size from monomers to long-chain polymers, such as catechin, epicatechin, and procyanidin B2. Because of its different properties, grape seed extract (GSE) has been proposed to be a good nominee for decreasing metabolic and cardiovascular changes related to obesity and metabolic disorders. 45 Ingle et al evaluated E1, E2, estrogen conjugates, androstenedione and testosterone levels in 191 women who were treated with anastrozole 1 mg/day as adjuvant therapy for resected early BC. Their results showed large interindividual variation in anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. The authors suggested that this commonly used agent for the treatment of BC should be evaluated in pharmacogenomics studies aimed at identifying genetic variation in drug metabolism. A similar mechanism could be responsible using GSE as an AI. 46 Proflavanol is a plant derived antioxidant combined with extracts from grape seeds. It actually helps your body remove waste (free radicals) produced by cells when they use oxygen.Also, it increases blood circulation to the pelvic area, decreases inflammation, and reduces the impact of stress on the body. The overall effect of these changes is an enhanced uterine environment that is better prepared for implantation and a healthy pregnancy.
Growing evidences demonstrated that the supplementation of GSPE as an antioxidant is an efficient measure to reduce the oxidative stress in the ovary. The protective effects of GSPE against oxidative stress on natural aging ovarian tissues. Thus, GSPE has an effect on the sexual health of woman and can be used as a potential herbal medicine.

L-Arginine:
Nitric oxide (NO) has been well established as the key mediator for the up-regulation of cyclic guanosine monophosphate (cGMP) which in turn mediates circulation and sexual function. L-arginine is a precursor of NO.
The conversion of L-arginine to NO is mediated by nitric oxidesynthase (NOS). Increasing tissue L-arginine levels result in the increase of NO and cGMP. Supplementation with L-arginine has been shown to play a role in restoring endothelial-derived NO production in many disorders which reduce or impair this production, including diabetes, hypercholesterolemia, and mechanisms related to hypertension. Studies also point to the role of L-arginine in reducing cell-mediated breakdown of NO. 47 Nitric oxide synthase (NOS) is present in the deep arteries, veins, and capillaries of the human vagina. NOS fibres related to vascular smooth muscles are also found in the vagina of the cow, pig, and mouse. Such location suggests that nitric oxide plays a role in the control of vaginal blood flow and/or vaginal contractile activity. In this view, the downregulation of NOS in the rat vagina upon estrogen withdrawal may be significant to the pathophysiology of female sexual dysfunction. 48 The proposed mechanism of enhancement of the nitric oxide (NO) pathway with Larginine only explains these results. NO derived from L-arginine is central to smooth muscle relaxation, vascular dilatation, and the regulations of circulation. 49 VasoactiveIntestinal Polypeptide(VIP) areabundant in the vagina, where they innervate bloodvessels and smooth muscle in the vaginal wall, andform a plexus beneath the epithelial layer. The highest levels of VIP in the femalereproductive tract are found in the vagina and cervixwith lower levels in uterine and fallopian regions. Physiologically, VIP has been implicated in thevaginal vasodilatation and transudation, or vaginallubrication, that occur during sexual arousal. Neuropeptide Y (NPY) is alsoabundant in neurons in the human female genitaltract, and is contained in nerves innervating bloodvessels, as well as in nerves that form a subepithelialplexus. 50 NPY and VIP are well established as vasomotorneurotransmitters, being involved in neural control ofblood flow. In the human and guinea pig uterineartery NPY causes vasoconstriction while VIP causes vasodilatation ofvaginal blood vessels. NO was first established as asubstance released from endothelial cells to causevasodilatation, but it too canbe released from nerves innervating the uterine artery,thereby mediating vasorelaxation. The distribution of neuronal NOSwithin nerves innervating the human vagina has notbeen previously demonstrated, but in the wall of themouse vagina NOScontaining nerves form a densenetwork, and intrinsic ganglion cells may also befound, as well as a dense subepithelial plexus, andperivascular localisation. 50 From studies on laboratory animals it has beensuggested that nitric oxide (NO) may also function asa neurotransmitter in male and female genital organs,including the uterus and vagina.NO is likely to have asensory role, since NOS has been found in asubpopulation of sensory neurons in the DRG(dorsal root ganglia) ofhumans, monkeys and rats. 50 The NO-cGMP pathway plays a key role in the male and female genital sexual arousal response.Nitric oxide synthase (NOS) utilizes L-arginine and oxygen as substrates to produce nitric oxide (NO).Arginase is a metalloenzyme that catalyzes the hydrolysis of L-arginine to produce L-ornithine and urea. It isproposed that arginase competes for L-arginine and reduces NOS activity in genital tissues, thus modulating sexual function. Using 2 transition state analogue inhibitors of arginase, 2(S)-Amino-6-boronohexanoic acid (ABH) and S-(2boronoethyl)-L-cysteine (BEC) have been characterized arginase activity in penile and vaginal tissue. Neither of these inhibitors has activity against NOS. Thus, ABH and BEC are useful compounds for examining the role of arginase in genital tissue physiology, without directly influencing NOS activity. We present data to suggest that arginase may regulate NO production by competing for endogenous pools of L-arginine. In this fashion, arginase is an indirect regulator of penile and vaginal blood flow and specific arginase inhibitors may improve genital blood flow during sexual arousal. As evidenced by the upregulation of arginase in specific disease states, its distribution in the vagina, and its modulation by sex steroid hormones, this enzyme may also participate in numerous other physiological and pathophysiological processes, such as tissue growth, fibrosis, and immune function. 51 Thus, the potential role of nitric oxide in mediating vaginal sexual response should not be underestimated.

Part II: Effect of Soy Isoflavones, Tribulus terrestries, Mucunapruriens, L-Arginine, Grape Seed Extract, on Menopausal Women:
In developed countries, communities and midwives are showing a renewed interest in the use of herbal and alternative medicine. Western oriented medicine and health systems, introduced during the colonial era, did not eliminate well-established systems of traditional medicine and many Africans learnt to use both health systems depending on the availability or the nature of the illness. Drugs obtained from natural sources are perceived to have the least risk and low side effect profiles, while having the ability to cure medical disorders in much the same way as their synthetic counterparts. 59,60 Phytoestrogens are a group of biologically active compounds that can play an important role in maintaining hormone balance and overall health. Their health benefits are attributed to mechanisms that influence estrogen receptor sites, sex hormone binding globulin, cell proliferation, angiogenesis, cholesterol synthesis, and platelet aggregation, in addition to antioxidant and anti-inflammatory properties. Because of their estrogenic activity, phytoestrogens are particularly important for women hence, they provide many of the health benefits of hormone replacement therapy, such as protecting against cardiovascular disease and osteoporosis, while simultaneously protecting breast tissue. 61,62 Soy Isoflavones: Soy isoflavones are nonsteroidal molecules structurally and functionally related to 17β-estradiol. Three major isoflavones found in soybeans are genistein, daidzein, and glycitein. When they bind to estrogen receptors α and β via their phenolic rings, they may exert agonistic, antagonistic, or partially agonistic/antagonistic effects at the receptor. Isoflavones occur in soybeans as glucosides. When they are consumed, they undergo metabolic changes in the gastrointestinal system. A sugar moiety is removed, and metabolically active aglycons form.One third of aglycon is absorbed as free isoflavone, and two thirds are converted to metabolites such as equol and p-ethylphenol by the intestinal microflora, which are also absorbed. Both free and metabolizedisoflavones are excreted by the kidney within 24 hours. Metabolism of isoflavones is also influenced by other components of the diet. A diet rich in carbohydrates results in extensive biotransformation of isoflavones and leads to greater amounts of equol. In the presence of antibiotics that alter intestinal microflora, the metabolism of isoflavones is reduced. 52 Interest in investigating potential benefits of isoflavones onbone mass came from the data on bone-sparing effects of asynthetic isoflavone, ipriflavone, which has been shown inseveral studies to suppress bone resorption, increase calciumretention in bone, and augment the effects of estrogen onbone. Ipriflavone is structurally similar to soy isoflavones.One of its metabolites, daidzein, is responsible for anestimated 10% of the actions of ipriflavone. Therefore,ipriflavone in doses between 600 and 1,200 mg/d seemedan alternative to MHT(menopausal hormone therapy) for postmenopausal women. However,a recent 3-year multicenter study established that it is nobetter than placebo in preventing bone loss and bonefractures inpostmenopausal women, and some womendeveloped lymphocytopenia during ipriflavone treatment. 53 Genistein increased bone formation, osteoblast number, andosteocalcin level and blocked the increased production ofTNF-α, which might be responsible for bone-sparing effectsof genistein. Another possible mechanism of genistein isthought to be through the regulation of B lymphopoiesis. Blymphocytes increase after ovariectomy and secrete TNF-α,IL-1, and IL-6, which are involved in bone loss related toestrogendeficiency. 54 In 2005, the NIH's National Institute of Environmental Health Sciences held a workshop to determine whether phytoestrogens could affect hormonal balance in animals and to address the problem and provide guidance 811 concerning the varying estrogen content in commercial diets for laboratory animals. The report determined that study results are confounded by unforeseen levels of isoflavones in animal diets and that the significant variability in estrogenic content between batches resulted in differences in experimental outcomes. The report also concluded that the obvious differences in dietary estrogenic components of soy supplements and tablets could also confound results of clinical studies and questioned the quality of data obtained in human studies. 55 Tribulus terrestries: FSH output and ovulation in infertile women, while the cellular mechanism of this effect remains largely unknown. Rabbits fed Tribulus terrestries extract exhibited differences in the expression of oocyte-derived factors, bone morphogenetic protein 15, and growth differentiation factor 9, which are presumed to participate in controlling follicular development and ovulation. 56 Tribulus terrestriesprevents the developmentof ovarian cysts and polycystic ovarian syndromes in ratsand women.
These observations indicate that Tribulus terrestries canpossibly affect female reproductive functions; however, the studiesconducted to date have demonstrated that this plant affectsreproductive functions in healthy females, whether the effects onovarian functions are mediated directly or via upstream hypothalamo-hypophysial and/or peripheral hormonal regulators or whetherpuncturevine can affect ovarian responses to hormonal regulators. 57 Steroidal saponins may be responsible for the intrinsic hormonal activity of Tribulus terrestries, directly stimulating the endocrine-sensitive female tissues such as the uterus and vagina. It has been proposed that the active components of Tribulus terrestriescan be converted enzymatically into weak androgens similar to DHEA, which could, in turn, be converted intomore powerful androgens such as testosterone in the gonads and peripheral tissues. 58 Tribulus terrestrieswas more effective in alleviation of menopausal transition symptoms and overall improvement in health-related quality of life. It can be a safer alternative to hormone replacement therapy.

Mucunapruriens:
On phytochemical analysis, the seeds of Mucunaprurienscontain high concentrations of L-DOPA. Other constituentsinclude gluthathione, lecithin, gallic acid, beta sitosterol, nicotine, dimethyl tryptamine. The leavesalso contain 0.5% L-DOPA. 63 The plant is used against a wide range of conditions whichinclude neurological, menstrual disorders, urinary tract problems, fever, ulcers and constipation. It is alsouseful as a hypoglycemic, vermifuge, antihypertensive and carminative agent. 64 In a study, an increase in the wet weight and dry weight of uteri in standard and the test group of mice proves to be the estrogenic activity of ethanolic extract of Mucunapruriens. It is also supported by the results obtained by others researchers too. Administration of estrogenor progesterone to adult or ovariectomised rats is known to elevate significantly wet weight of uterus, cervix and vagina albeit the estrogen is found to exert more pronounced action. 65 Mucunapruriens, also known as Velvet Bean, Mucuna pruriens has been used for centuries by Ayurvedic herbalists for overall wellness. Mucunapruriensprovides support for brain function, muscle health and libido. Mucunaprurienshas also been shown to have diuretic effects. It increases tissue resiliency and improves coordination. Mucunapruriens can also increase testosterone levels, which in turn can lead to increased muscle mass and strength. It also supports the nervous and reproductive systems in the body. anti-oxidant activity of Mucunaprurienshas been also demonstrated in vitro by its ability to scavenge DPPH radicals and reactive oxygen species. This is an excellent natural source of L-dopa and 5-hydroxy tryptophan (5-HT). 66

L-Arginine and Grape Seed Extract:
The regulatory role of nitric oxide (NO) in vaginal has been studied by the researchers since long time. We used specificinhibitors of enzymes in the NO-cyclic GMP (NO-cGMP) pathway and investigated their effects onvaginal blood flow in the rabbit. NO synthase (NOS) activity was similar in both the proximal anddistal rabbit vagina; whereas, arginase activity was 3.4-fold higher in the distal vagina. Intravenousadministration of the NOS inhibitor L-NAME resulted in a 66% reduction in genital tissueoxyhaemoglobin and a 53% reduction in vaginal blood flow. This attenuation occurred despite a20-30% increase in systemic arterial pressure. 67 Nitric oxide (NO) is an endogenous anti-atherogenic molecule. Endothelial dysfunction, resulting from depressed NO bioavailability, has been demonstrated in the presence of atherosclerotic risk factors, [68][69][70][71] even in the absence of angiographic evidence of atherosclerosis. 69,71 Moreover, the magnitude of coronary endothelial dysfunction was a potent predictor of major cardiovascular events. 72 Finally, interventions improving NO bioavailability, such as cholesterol lowering, 73 are able to favourably affect prognosis. Therefore, correction of endothelial dysfunction is of potential clinical relevance. Ageing, a potent cardiovascular risk factor, is associated with progressive impairment of endothelial function. This has been proven for various indices of endothelial function, such as vasodilatory responses to acetylcholine or methacholine in the epicardial arteries, coronary and 71,74,75 resistance vessels, as well as the contribution of NO to acetylcholinemediated forearm 76 and coronary dilationand to basal vascular tone within the forearm 77 and coronary circulation. Flow-mediated dilation of the brachial artery is a useful non-invasive index of endothelial function, whichis decreased in the presence of atherosclerotic risk factors, including age even in the subjects without known other risk factors, 78 as well as in the elderly without clinical evidence of cardiovascular disease.
Local intra-arterial administration of l-arginine, a substrate for NO synthesis, is known to improve impairedendothelial function within the coronary and forearm vascular beds in healthy old age, but without effect inyounger subjects with normal endothelial function. 79 NO is synthesized in endothelial cells from the amino acid L-arginine by the enzyme endothelial NO synthase (eNOS). NO rapidly diffuses to vascular smooth muscle cells where it stimulates soluble guanylate cyclase, inducing cGMP-dependent vasodilation. Thus, reduced NO bioavailability following physiological stimulation of arterial endothelial cells manifests as impaired arterial dilation. 80 Another non-hormonal and effective treatment are pure, uncontaminated grape seed extract. A 2014 study of 96 menopausal women aged 40 to 60 received either placebo, or grape seed extract in low dose (100 mg/day) or high dose (200 mg/day). The study was randomized, double-blind, and lasted eight weeks. In the high dose group, there were significant improvements in physical symptoms, hot flashes, insomnia, anxiety, and depression. In both the low dose and high dose groups, blood pressure decreased and muscle mass increased. 81 Grape seed extract contains a potent class of polyphenol antioxidants known as proanthocyanidins, which do not bind to estrogen receptors. These antioxidants have been studied for their analgesic, anti-infammatory and heartprotective abilities. One proanthocyanidins-rich pine bark extract was found to alleviate menopausal symptoms. Grape seed may prove even more effective, since the proanthocyanidins extracted from grape seed have a higher molecular weight than those extracted from pine bark. That may be why, unlike pine bark, 200 milligrams daily of grape seed extract led to remarkable improvement in anxiety. 81 Grape seed is one of the richest sources of proanthocyanidins which are polymers offlavan-3-ols with an average degree of polymerization between2 and 17. Previously, we showed that grapeseed extract (GSE) has anti-oxidative activity, including the abilityto scavenge free radicals. Besides itsanti-oxidative property, it has been suggested that GSE has anti-inflammatory, anti-diabetic, anti-obesity, anti-carcinogenic, andanti-aging effects. 82 The role of estrogens in breast cancer (BC) development is widely accepted, leading to the development of selective estrogen receptor modulators and aromatase inhibitors for BC treatment and prevention. However, because of potential adverse effects, healthy women with high risk of BC are hesitant to take them. Preliminary evidence from animal studies shows that grapes may have an aromatase-inhibiting effect, decreasing estrogen synthesis and increasing androgen precursors. We conducted a randomized, double-blind, dose-finding early-phase trial on the effect of grape seedextract (GSE) on estrogen levels. Postmenopausal women who met study inclusion criteria (N=46) were randomly assigned to daily GSE at a dose of 200, 400, 600, or 800 mg for 12 weeks. Primary outcome was change in plasma levels of estrogen conjugates from baseline to 12 weeks posttreatment. Thirty-nine participants (84.8%) completed thestudy. GSE in the 4 daily doses did not significantly decrease estrogen or increase androgenprecursors. 83 That means GSE has the effect on estrogen levels at some point. If taken regularly at set dose, that is effective in menopause than it can have the better effect on the menopausal symptoms.