Ovarian Factors of Cardiovascular Disease: The Way to Go?

Abstract

The function of the female reproductive system is critically dependent on the general health of a woman. However, the activity of ovaries has its projection on metabolic processes, vascular tone, and endothelial function. Hyperandrogenicity in polycystic ovarian disease is a trigger for adiposity, diabetes type II, and atherogenic vasculopathy. The increased level of testosterone persists to stay even after menopause. The data on hormonal changes during menopause is discussed. Hormone replacement therapy did not demonstrate an evident beneficial effect on the cardiovascular system. The possible therapeutic strategy for improved cardiovascular health during the transitional year of life is presented. The use of diet, L-arginine, and xylitol could be a reasonable option in the management of perimenopausal women.

1. Introduction

Cardiovascular disease (CVD) takes a special place among all challenges and issues of humankind. This fact is due to a wide range of risk factors for increased blood pressure (BP), numerous pathogenic mechanisms in the scenario of arterial hypertension, as well as age and gender features of this pathology. The autonomic and endocrine regulation of BP has certain differences in female and male persons. Since the functioning of the female reproductive system has an obvious hierarchical organization, it is necessary to consider the main mechanisms of regulation that ensure the participation of the ovaries in the processes of homeostasis. The hypothesis of “fetal programming” explains the role of the antenatal period in the development of diseases during adulthood [1]. However, the manifestation of systemic atherogenic vasculopathy before menopause is minor. Therefore, hypoestrogenicity could be a trigger for CVD in women.

The continual search for the regulation of the female reproductive system contributed to the discovery of a number of fundamental methods of diagnosis. Stockard and Papanicolaou described changes in the vaginal mucous layer depending on the phase of the menstrual cycle, which was known as a hormonal colpocytology in 1917 [2]. Rock and Bartlett proposed the use of endometrial biopsy for the detection of the phase of the ovarian cycle in 1937 [3]. Netter used this method and demonstrated the relationship between the endometrium changes and the phase of the ovarian cycle [4]. Allen and Doisy found the effect of follicular fluid extract on the morphological changes of the vaginal mucosal layer in female mice in 1923 [5]. Corner and Allen isolated progesterone in the same year. They definitely indicated the site of production of estrogens (Graafian follicles) and progesterone (corpus luteum) in 1929 [6]. A new milestone in the study of the functional properties of the ovaries was the research performed by the Swedish scientist Bent Falck in 1959. Bent Falck delivered a report “The use of micrografts to determine the site of estrogen production in the ovaries of rats” at the medical faculty of the University of Lund. He evidently supported that estrogen and androgen secretion occurs only in transplants containing cells of the theca interna and interstitial cells together with granulosa or corpus luteum cells (the so-called “two-cell theory”) [3].

The research of the gynecologists from Chicago Irving Stein and Michael Leventhal “Amenorrhea associated with bilateral polycystic ovaries” was of great theoretical and practical value. According to the primary source, polycystic ovary syndrome (PCOS) is “menstrual irregularity, including amenorrhea, infertility, hirsutism, somewhat delayed development of the mammary glands, and obesity.” The authors found that ovarian resection improved the condition of patients and led to the restoration of a normal menstrual cycle [7]. PCOS is extremely widespread in the modern female population and leads to significant short- and long-term consequences, such as hyperandrogenism, insulin resistance, impaired carbohydrate metabolism, obesity, chronic inflammation, endothelial malfunction, dyslipidemia, and arterial hypertension. These pathological processes are involved in the pathogenic pathways of diabetes mellitus (DM) type 2, coronary heart disease, and brain stroke [8]. The lack of ovulation and ovarian hyperandrogenicity are typical for patients with PCOS. The presentation of metabolic disorders in this population allows us to think about the relationship between hyperadrenogenicity and disturbed carbohydrate metabolism in women with PCOS [9].

The impaired follicle maturation is one of the mechanisms of hyperandrogenicity in women with PCOS. The follicles do not reach the preovulatory level. This is due to the low concentration of FSH, which does not elevate enough to the necessary threshold level for the aromatase activation and the synthesis of estrogens. The activity of the androgen fraction dominates. The anti-Müllerian hormone (AMH) reduces the sensitivity of granulosa cells to FSH. AMH is a glycoprotein and belongs to transforming growth factor-β. The concentration of AMH in women with PCOS is three times higher than in healthy persons [10]. Obesity, insulin resistance, and hyperandrogenicity have been shown to play a significant role in elevated AMH in some studies [11, 12].

The history of PCOS lasts for about 40 thousand years according to the theory of Aziz [13]. The unbeneficial living conditions of people during the Paleolithic period led to the suppression of fertility and the accumulation of fat. The wave of migration of primitive people from Africa to Europe showed the need to survive in conditions of cold winters and food shortages. The storage of additional energy supply was achieved by an increase in the insulin level and excessive development of adipose tissue. Declining fertility also increased the chances of survival for women at that time. Therefore, PCOS contributed to the preservation of humanity and is an endocrinopathy of the surviving descendants of insulin-resistant ancestors.

The etiology of PCOS is still unknown. The occurrence of this pathology could be associated with hereditary reasons. However, the specific genes related to PCOS are not found. Barker’s theory of fetal programming captures the effect of excessive androgen levels on the fetus that contribute to metabolic disorders in adult life. This is due to reprogramming at the genetic level and subsequently causes the manifestation of oligo-anovulation, polycystic morphology of the ovaries, and insulin resistance [14]. The risk of metabolic syndrome X, DM type 2, and CVD was twice as high in women with PCOS relative to the general population [15]. The negative effect of testosterone on the fetus was found in an experimental animal model. The increased incidence of metabolic disorders similar to PCOS was found [16]. However, the human embryo is protected from excess maternal androgen levels by a combination of high concentrations of androgen-binding proteins and significant aromatase activity in the placenta. Placental aromatases take part in the transformation of maternal androgens into estrogens (mainly estriol). Nowadays, it has already been proven that maternal hyperandrogenicity can cause hyperproduction of fetal sebaceous glands, which persists during the neonatal period. Thus, fetal programming associated with high androgen concentration may be a significant etiological factor of PCOS.

The main branches in the pathogenesis of PCOS are insulin resistance and chronic inflammation. Women with PCOS have an increased risk of metabolic syndrome X and CVD. The odds ratio (OR) of CVD in women with PCOS is 1.3–2.0 in several meta-analyses [17]. Premenopausal age is an additional factor that increases the risk of systemic vasculopathy. Obesity is known to be associated with insulin resistance and inflammation. Thin women with PCOS do not have an increased risk of DM type 2, but the risk of CVD is currently being investigated [18]. All women with PCOS are recommended to be screened for the markers of metabolic syndrome. However, the study of lipid profiles in young patients is not often informative and has no influence on treatment strategy. The most important prognostic markers for the development of CVD are elevated blood pressure, hyperglycemia, and dyslipidemia. The risk of CVD can be reduced under the influence of drug therapy. At the same time, the fasting insulin level remained stable under the influence of combined oral contraceptives (COC). However, the use of COCs causes an increase in thrombin concentration and the risk of thromboembolic complications. Thus, COC use increases the chances of CVD [19].

A recent study found that the relative risk (RR) of arterial hypertension and dyslipidemia in women with PCOS was 1.7. CVD in obese women in this study was 2.4 [20]. It was also found that more than 30% of patients with PCOS had blood pressure ≥ 130/85 mmHg. Women with PCOS also had signs of hypertension, dyslipidemia, hyperglycemia, and hyperinsulinemia in the Chinese study [21]. In total, 18% of women with PCOS had an elevated level of triglycerides (>1.7 mmol/l). It has been confirmed that insulin resistance contributes to CVD. When BP increases, lipid profile and pancreatic β-cell function deteriorate in women with PCOS in the process of aging. It is also very important that the body mass index (BMI) was very different in patients with different phenotypes. Phenotype A is featured by hyperandrogenism, anovulation, and polycystic ovarian morphology. The last sign is absent in women with phenotype B. Phenotype C is the so-called “ovulatory” PCOS (characterized by hyperandrogenism and polycystic ovarian morphology). Phenotype D is called “non-androgenic” PCOS (ovulatory dysfunction and polycystic ovarian morphology). Recently, it has been established that the level of AMH reflects the severity of PCOS. The most difficult is the combination of phenotype A with a high level of AMH. However, there is no clear correlation between AMH concentration and insulin resistance. One Chinese study found that AMH is a valuable prognostic marker for insulin resistance [22].

Hypertrophied adipocytes are known to have a significant number of genes involved in inflammation and cytokines production. The presence of tissue hypoxia may contribute to the accumulation of macrophages and other immune cells in adipose tissue. Inflammation in adipose tissue causes a disturbed hepatic carbohydrate metabolism and reduces the sensitivity of skeletal muscles to insulin. All patients with PCOS have elevated levels of inflammatory markers: IL-6 and C-reactive protein (C-RP). Proinflammatory cytokines: TNF-α, IL-6, and IL-1β have a paracrine effect that contributes to insulin resistance. It is also known that an elevated blood level of pro-inflammatory cytokines is involved in the development of atherosclerosis and CVD [23]. IL-18, TNF-α, IL-6, and C-RP are the main markers of inflammation occurring in women with PCOS. It is quite interesting that both thin and fat women have increased levels of pro-inflammatory substances that contribute to the development of insulin resistance, atherosclerosis, and hypertension. It has been known for more than 10 years that women with PCOS have elevated levels of C-RP. This dependence increases with age and body weight growth. It can be considered that a high concentration of C-RP is a marker of increased risk of CVD in women with PCOS. IL-6 is also considered a risk indicator of atherosclerosis, coronary heart disease, and hypertension. IL-6 is known as a potential inducer of C-RP synthesis by hepatocytes. The increase in the concentration of C-RP supports the severe atherosclerotic process, and the risk of myocardial infarction and stroke [24]. IL-6 and C-RP levels are elevated in women with PCOS and insulin resistance. Since leukocytes are located in visceral adipose tissue and these cells are a source of pro-inflammatory cytokines, it can be assumed that insulin resistance is a factor contributing to the excessive activity of leukocytes. The correlation between C-RP, IL-6, and body mass index (BMI) was found. It is possible that the use of C-RP testing is an important addition to the traditional CVD risk screening in women with PCOS. The elevated proinflammatory cytokines may be an early marker of insulin resistance and atherosclerosis. There are also other known markers of inflammation in women with PCOS. Chemerin affects metabolic risk factors and blood pressure. The level of this novel adipokine is increased in women with hyperandrogenicity. The elevated levels of visfatin were found to be associated with beta-cell damage in type 2 DM. The visfatin level is elevated and correlates with body mass index, insulin resistance, and hyperinsulinemia in patients with hyperandrogenicity [25]. The increased concentrations of vaspin, leptin, and resistin were also found. However, the level of irisin (“hormone of physical activity”) is reduced in this category of patients. This myokine improves cognitive impairment [26]. Therefore, menopause contributes to the development of metabolic syndrome X.

Adrenomedullin, natriuretic peptide, and copeptin were found to participate in the regulation of fluid balance and hemodynamic processes by modulating vascular tone and diuresis. These substances may play a significant role in the pathogenesis of arterial hypertension in women with PCOS [27]. Adrenomedullin is known to be produced by smooth muscle cells and endothelial cells and is distributed throughout the body. It is also considered an adipokine because it can be produced by adipose tissue. Adrenomedullin secretion increases in response to inflammation, hypoxia, and insulin resistance in CVD and DM type 2. It is known that natriuretic peptide is released from cardiomyocytes in case of heart failure and as a result of adrenergic stimulation. Natriuretic peptide causes vasodilatation, stimulates natriuresis, and suppresses the activity of the renin-angiotensin-aldosterone system, reducing the effects of adrenomimetic substances. Natriuretic peptide stimulates lipolysis. An increase in the concentration of this substance is observed in CVD and heart failure [28]. However, obesity and insulin resistance have been shown to decrease natriuretic peptide levels in a large cohort study. The release of copetin captures vasopressin activation. Copeptin is more stable to measure than vasopressin and also reflects osmolality. Copeptin has certain prospects as a marker of myocardial infarction in combination with troponin. It has been established that an increase in the concentration of copeptin in heart failure worsens the prognosis. Copeptin also increases with obesity [29]. The significant value of studying the level of adrenomedullin, natriuretic peptide, and copeptin for predicting CVD in PCOS has been established.

A high risk of CVD in women with PCOS is typical for patients with obesity, arterial hypertension, dyslipidemia, impaired carbohydrate tolerance, and a family history of CVD. An increased BMI plays the most important role among all risk factors for arterial hypertension. The risk of systemic vasculopathy and kidney disease is very high in women with metabolic syndrome X [30]. Therefore, all patients with PCOS in addition to a gynecological examination should be examined by a general practitioner, a cardiologist, an endocrinologist, and a neurologist. This is the basis of an interdisciplinary approach to the management of women with PCOS. This strategy provides an individual CVD prevention program. Thus, the prevention of CVD in women with PCOS includes screening for metabolic syndrome X (BMI, BP, lipid profile, and carbohydrate metabolism) even in young and thin women. There is evidence that metabolic disorders in PCOS are associated with IL-6 gene polymorphisms and can be corrected with lifestyle changes and metformin use.

The majority of middle-aged women suffer not only from decreased levels of estrogen but also testosterone insufficiency. The use of testosterone is a possible therapeutic option for women during their transitional period. However, the declined level of testosterone is associated with suppressed libido and, therefore, is known as a reason for sexual dysfunction [31]. However, hyperandrogenicity in women with PCOS persists even after menopause and elevates cardiometabolic risks [32]. The topical or systemic use of estriol or estradiol could stimulate the proliferation of vaginal epithelium and interfere with vulvovaginal aging. But estrogens have no influence on libido. Since the prescription of testosterone preparations is out of label in the majority of cases, the possible risks and adverse effects of testosterone in female organisms should be discussed. The lack of information about dosage, forms, and duration of testosterone administration is linked to insufficient research data.

Nowadays, the vaginal use of hyaluronic acid becomes very popular. The application of hyaluronic acid gel was found to decrease vaginal dryness, itching, and bleeding, and improve sexual function in women of the transitional period [33]. Therefore, hyaluronic acid is an alternative for hormone treatment of atrophic vaginitis.

The main target population for testosterone use is transgender individuals. These persons could be the model for the investigation of systemic male steroid application in female organisms. The problem is that these patients are younger than perimenopausal women. However, the available experience demonstrates all possible advances and complications of testosterone clinical use [34]. The prescription of testosterone is logical only in case of vaginal atrophy. Testosterone is known to increase hemoglobin levels due to its potency to stimulate bone marrow and elevate the production of erythropoietin in kidneys. Several studies showed that testosterone increased hemoglobin levels in patients with unexplained anemia [32]. Androgens and estrogen are involved in inflammatory pathways. Sexual steroids have immunosuppressive and anti-inflammatory activity. Testosterone was found to modulate renal perfusion and, therefore, could produce an acute kidney injury. The elevation of creatinine was found in transgender individuals in the process of testosterone administration [35]. Thus, the possible nephrotoxic action of testosterone must be kept in mind. The effect of testosterone on cognitive function and mood is not completely known. The impact of this substance on muscle strength, body fat, and mineral bone density is not evident. Systemic use of testosterone in perimenopausal women was found to increase acne but not related to hair loss. Oral testosterone therapy is associated with an adverse lipid profile and, therefore, should be avoided in women with cardiometabolic risks [36]. However, transdermal use of androgens is possible therapeutical management for women with decrease in testosterone.

The first step in lifestyle modification is a diet, regular physical training, and cessation of smoking. It has been proven that the loss of excess weight in patients with PCOS leads to an improvement of the lipid profile, normalization of carbohydrate metabolism, reduction of hyperandrogenism, and restoration of ovulation. It is necessary to reduce body weight by 20% for women with morbid obesity [37].

Pharmacotherapy includes drugs that increase insulin sensitivity, and lower cholesterol, BP, and body weight. Metformin has the longest history of use for the treatment of insulin resistance. Due to its multipotent effect, this drug is often called the “aspirin of the XXI century.” Metformin is prescribed as the first line of therapy, especially when the patient refuses to lose weight. The drug should be taken during meals because, on an empty stomach, it can cause symptoms of irritation of the gastrointestinal tract (sometimes it can cause diarrhea). Metformin does not have a significant effect on body weight but improves the lipid profile. It was also found that the use of metformin contributes to a decrease in the level of C-RP and prevention of atherogenic vasculopathy. However, the main indications for prescribing metformin are insulin resistance and hyperinsulinemia. Several studies have been conducted that proved the same antiandrogenic effect of metformin and the combined oral contraceptive with cyproterone acetate [38]. The level of side effects of the combined oral contraceptive such as increased body weight, increased BP, depression, headache, and chest pain was significantly higher. However, combined oral contraceptives are more effective in regulating the menstrual cycle compared to metformin.

There has been a growing interest in the use of vitamin D₃ as a factor that improves insulin resistance, chronic inflammation, and oxidative stress in patients with PCOS for the past decades. Several studies in vitro showed a decrease in the synthesis of pro-inflammatory cytokines and an increase in the concentrations of anti-inflammatory substances [39]. At the same time, the anti-inflammatory effect of vitamin D₃ has been confirmed in some clinical studies. A recent meta-analysis presented data from seven clinical trials of vitamin D₃ in women with PCOS. Vitamin D₃ supplementation in women with PCOS reduced C-RP and malondialdehyde levels, and increased antioxidant capacity in this meta-analysis [40].

If the level of low-density lipoprotein is more than 160 mg/dl, and the concentration of very low-density lipoprotein is more than 190 mg/dl, pharmaceutical correction with a drug that lowers the cholesterol level should be started. Statins are the most often used. Many studies have shown that statins decrease low-density lipoprotein levels, and testosterone concentrations, reduce insulin resistance, and improve endothelial function. Antihypertensive drugs should be prescribed when blood pressure rises above 140/90 mm Hg. The level of BP about 120/80 should be considered the optimal one that prevents the incidence of complications. The experience of the drug application for weight loss sibutramine in women with PCOS is known [41]. It was established that sibutramine reduces body weight and the concentration of insulin, testosterone, and triglycerides. However, the level of evidence for these results is insufficient for inclusion in recommendations for women with PCOS. The use of inositol and resveratrol, as well as naltrexone, is promising. The first two of these drugs have a positive effect on carbohydrate metabolism and increase the antioxidant potential [42]. Naltrexone is a centrally acting drug, and its use, although it does not yet have a sufficient evidence base, could be the initial step in a neuroendocrine approach to the treatment of PCOS. The experience of gastric banding is also known, which contributes to the normalization of metabolic processes, and correction of BP in women with obesity refractory to pharmacotherapy.

Unfortunately, HRT is not recognized as an efficient method for metabolic syndrome X prevention [43]. Since metabolic disorders reduce the active working capacity and life period in general, it is necessary to develop a therapeutic strategy focused on their negative impact on a woman’s health prevention or reduction. Women with a normal weight before the onset of menopause should be recommended to increase physical activity, and obese patients should be asked for a diet [44]. Diet was found to be associated with a reduction in incident cardiovascular and coronary adverse events, as well as heart failure. The daily consumption of 400 g of vegetables for 3 weeks was found in one study to improve lipid metabolism and glycemic control in obese menopausal women [45]. The Mediterranean diet may help in the primary prevention of bone, metabolic, and cardiovascular diseases in the postmenopausal period [46]. Interestingly, CVD risk in postmenopausal women appears to be sensitive to a change to a low-fat dietary pattern and, among healthy women, includes both coronary heart disease benefit and brain stroke risk [47]. The existing experience of wellness anti-aging programs indicates the use of medical nutrition and physical education. However, the issue of emotional and physical comfort in the process of weight loss remains open.

The state of moderate ketosis is known to reduce the patient’s appetite in the process of medical diet therapy [48]. However, ketosis leads to the predominance of anaerobic glycolysis, the accumulation of lactate, and lipid peroxidation tissue products. This supports oxidative stress and adversely affects hepatic lipid metabolism. Increased ketogenesis is dangerous for people with DM and requires adjustment of insulin dose or a sulfonylurea drug. How can these deviations be prevented? The obvious prospect is the use of xylitol preparations, which are not an insulin-dependent source of energy and could prevent the transition from the Krebs cycle to other metabolic pathways.

Xylitol is known as a source of energy to achieve balance with an excellent anti-catabolic effect. Xylitol can reduce constipation, DM, obesity, and other diseases. This polyol has a stimulating effect on digestion and immune system. The level of xylitol was found to be used as a predictor of the prospect of weight loss without surgical interventions in patients with morbid obesity [49]. After the use of xylitol, the glycemia level stays constant, and the processes of gluconeogenesis prevail over glycolysis. The long-term experience of using xylitol in the food industry supports its anti-inflammatory and antibacterial effects. It is capable of counteracting the etiological microbial factors of gingivitis, pneumonia, and media otitis. The dose-dependent antimicrobial effect of xylitol is known. Xylitol can compensate for NADH deficiency in patients with hemolytic anemia. There is also evidence that xylitol can reduce the proliferation of cancer cells. Xylitol enhances the processes of lipolysis, contributing to the reduction of adipose tissue, and has a therapeutic effect on dyslipidemia. It protects the heart, liver, kidneys, and pancreas from the negative effects of oxidative stress. Xylitol promotes a better metabolism of calcium and phosphorus and prevents the occurrence of osteoporosis after bilateral oophorectomy in experimental animals. Xylitol was found to have a beneficial effect on gut microbiota and increased the absorption of phytoestrogens in another experimental study. These findings could support its possible use for the prevention and treatment of osteoporosis.

Prevention of endothelial malfunction is one of the main tasks of women in menopause management. Formerly, HRT was found to have a protective effect on endothelium [50]. But this effect is critically dependent on NO-system. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving cardiovascular health. The level of nitric oxide was found to be decreased in women of transitional age. The lack of this vasodilating agent induces vasculopathy. HRT is known to contribute to the restoration of the lipid profile, increase the activity of nitric oxide synthase, and release this powerful vasodilator from the endothelium. The level of nitric oxide synthase is the key to the vasorelaxant effect of estradiol. Since L-arginine is a substrate for the synthesis of nitric oxide, its use could be a promising option for women obtaining HRT. The application of L-arginine could provide anti-inflammatory, metabolic, and vasoactive effects [51]. L-arginine deficiency possibly plays a key role in the progress of endothelial malfunction after menopause. A combination of aerobic exercise and regular L-arginine intake contributed to decreased blood pressure (BP) and inflammatory markers in older women [52].

The development of a therapeutic and preventive strategy including HRT, physical activity, diet therapy, and the use of xylitol and L-arginine preparations could make a favor in improving the quality of life of women over 45 years old. Xylitol solution with micronutrients should be administered in the form of infusions from the first days of the reduction diet once for 5 days. Administration of L-arginine should be started intravenously at 200 ml once a day for a week, and then be continued in oral form for another 3 weeks. The results of 1-month and 3-month programs, including physical training, diet, xylitol, and L-arginine, were already reported [53, 54]. The findings showed a real prospect of such a strategy for life extension. But the emphasis should be done.

A total of 71 perimenopausal women were enrolled in the study. Thirty-six patients with or without periods from Group II received sequential or continuous combined HRT. Thirty-five women of transitional age (Group III) additionally to HRT received a diet, L-arginine infusions of 200.0 ml once daily for a week, 20 ml of oral L-arginine solution for 3 weeks, and also xylitol solution 200.0 ml once daily during the 5 days were included in Group III. A low-carbohydrate and mild-fat diet (less than 26% carbohydrates or less than 130 gm/day) was used in the study. The distribution of the nutrients was 20% carbohydrates, 40% fat, and 40% protein. This diet featured a low glycemic index, slow ketogenesis, and anti-atherogenic effects [55]. Thirty-five healthy reproductive-aged women were included in Group I (control).

The obtained results showed that obesity plays an important role in the pathogenesis of climacteric syndrome. The findings of the study demonstrated a moderate positive correlation between BMI and diastolic BP, BMI, and Cooperman’s score, BMI and glucose level, BMI and C-RP (Figure 1). The reduction of BMI was found in patients from Group III (Figure 2). The declining Cooperman’s score in these patients supported the opinion of the use of diet in the treatment of early menopausal disorders. The reduction of BP was possibly associated with improved metabolic profile of patient in Group III (Figure 3). But the effect could be also associated with autonomic tone restoration by reducing sympathetic regulation. The decrease of atherogenicity, improved carbohydrate metabolism, and complete history of chronic inflammation were found in perimenopausal women (Figure 3). These findings support available data on the relationship between insulin resistance, atherogenicity, and systemic inflammation.

Figure 1.

The correlation between BMI and diastolic BP, BMI and Cooperman’s score, BMI and glucose level, and BMI and C-RP.

Figure 2.

The changes in BMI, systolic BP, diastolic BP, and Cooperman’s score in group III.

Figure 3.

The level of triglycerides, atherogenic index, glucose, insulin, HOMA index, and C-RP before and after 3-month program.

Since the effect of HRT on BP is multifactorial, the use of estrogens is not definitely postulated. Some studies showed the increased risk of complications of CVD in elderly women who obtained HRT [56]. The proposed 3-month program demonstrated its positive vasoactive effect. This method of management for perimenopausal women has a positive synergistic with estradiol effect on endothelium. Thus, L-arginine donation could be thought of as an efficient intervention for an improved cardiovascular health in perimenopausal women. Thus, the use of diet, L-arginine, and xylitol could be an important supplement to HRT. The findings emphasize the possible options for the prevention of atherogenicity. Weight gain and increased BMI was the main factor for insulin resistance, atherogenicity, and menopausal disorders. The use of diet, xylitol, and L-arginine improved metabolic processes and reduced menopausal disorders [53, 54].

Weight gain was the main factor for insulin resistance, atherogenicity, and menopausal disorders. The use of diet, xylitol, and L-arginine improved metabolic processes and reduced menopausal disorders.

BMI in perimenopausal women was responsible for BP, menopausal Cooperman’s score, carbohydrate metabolism, and inflammatory response. The use of a 3-month program including diet, xylitol, and L-arginine solutions contributed to the reduction of Cooperman’s score, chronic inflammation, and restoration of lipid and carbohydrate metabolism. This program could help us to make another step in the march toward improved women’s health in their perimenopausal years.

Menopause is still in transition from conventional strategies to anti-aging medicine. Healthy aging could be provided only in case of the absence of serious diseases. CVD is a “destiny” for the postmenopausal women. The continual search in the field could help to provide completely safe and efficient interventions for longevity and stamina.