Women rarely suffer cardiovascular insult until perimenopause …

Berberine Overturns Menopause Comorbidities
With increasing lifespans, women are now spending as much
as one-third of their lifetime in postmenopausal state

By Will Block

P erimenopause is a relatively new term devised by healthcare professionals to identify what occurs for a woman as she moves closer to menopause. Many of the symptoms of perimenopause, marking the end of the reproductive cycle, are like those of premenstrual syndrome (PMS), but others are different. This is due in part to changes in hormones, the slowing of metabolism, and the subsequent decrease in life quality affecting each woman differently.

The Perimenopausal Challenge

The increased proportion of overweight and obese people in Western societies has been attributed largely to behaviors that include sedentary lifestyle and dietary excess. Consequently, women are at particular risk during perimenopause. That’s because obesity and being overweight are associated with many comorbid conditions that are major contributing factors to cardiovascular disease.

With increasing lifespans, women are now spending as much as one-third of their lifetime in the postmenopausal state. Consequently, the development of new strategies to improve the prevention and treatment of menopause-associated pathologies is an important topic in clinical practice and in lifestyle choices.

Women Are at Particular Risk for Comorbidities during Perimenopause.

What Can Be Done for Perimenopause?

The purpose of a recent review1 — researched, analyzed, and written by scientists at the Universities of Ferrara and Bologna in Italy — was to examine published studies of weight loss programs for perimenopausal women using behavioral change strategies of diet alone (including supplements), regular physical activity alone, or both in combination to determine the range of potential outcomes and reduction of cardiovascular risks. Based on the findings from this review, the authors recommend practical applications now and suggestions for future research.

Cardiovascular diseases represent the leading causes of morbidity and mortality in women after menopause and 56% of all causes of death in Western European countries.

Menopause Results in a Decrease in Life Quality

Menopause is characterized by an altered hormonal status, which begins in perimenopause, and results in a subsequent decrease in life quality affecting every woman differently.

Of the hormonal changes, the decline and eventual termination of estrogen production is of principal concern. This is typically associated with the onslaught of uncomfortable symptoms (hot flashes, night sweats, breast tenderness, vaginal dryness, irregular menses, mood changes, and vaginal atrophy) along with certain pathologies such as osteoporosis, heart disease, hypercholesterolemia, endothelial dysfunction, vascular inflammation, hyperglycemia, and depression.

Start Here: Hormone Replacement

Results from different studies indicate that the use of hormone replacement therapy (natural hormone replacement is best) in menopause needs to be carefully assessed. Also, the risks and benefits of the therapy ideally should be evaluated by each individual woman’s healthcare professional. Whatever the discipline, the professional should be knowledgeable about the importance of nutrition.

Simply put, the possible problems associated with hormone replacement therapy in a subpopulation of women may be lessened by other lifestyle modifications, such as diet, food supplements, and exercise. These may be safely used along with natural estrogens and progesterone. In recent years, there has been renewed interest in the potential of high quality natural products to provide health and medical benefits and to help prevent disease. For example, antioxidant compounds have been shown to be of great benefit in women experiencing menopausal symptoms.

Berberine Crosses Many Health Barriers

Berberine — a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids found in the bark, rhizomes, roots, and stems of assorted plants* — exhibits many different types of beneficial biological activities. Among them, the best-characterized ones are antioxidant, anti-inflammatory, cholesterol-lowering, antihyperglycemic, insulin receptor-sensitizing and antidepressive effects. The benefits of Berberine supplementation embrace the reduction of many menopause-associated pathologies. These include oxidative stress, inflammation and hypercholesterolemia-related cardiovascular diseases, hyperglycemia-related diabetes type 2 (hereafter “diabetes”), and depression.


*Sources of Berberine include Berberis [e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), Berberis aristata (tree turmeric)], Hydrastis canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense (Amur cork tree), Coptis chinensis (Chinese goldthread 黄连素 or Huang Lian Su), Tinospora cordifolia, Argemone mexicana (prickly poppy), and Eschscholzia californica (Californian poppy). See Wikipedia entry for Berberine.


Berberine Value for Oxidative Stress

The estrogen deficiency that accompanies perimenopause increases cardiovascular risk. This results from modifications of plasma lipid profile, activation of the renin-angiotensin system — a hormone system that regulates blood pressure and fluid balance — and overproduction of reactive oxygen species (ROS). ROS are generally formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis.

However, during times of environmental stress, ROS levels can increase dramatically, resulting in significant damage to cell structures. When the damage accumulates, this is known as oxidative stress.

Of relevance, oxidative stress is a serious imbalance between the ROS produced and the antioxidant systems, and has been identified as a cause of metabolic syndrome.

Menopausal women with severe symptoms have higher oxidative stress; thus it is possible to observe higher oxidative stress in menopausal women with metabolic syndrome and severe menopause related symptoms.

In general, too much ROS often precipitates pathological situations which can be highly injurious to adjacent structures in cells, including lipid membranes, DNA, and proteins.

Increased oxidative stress and reduced NO bioavailability are important contributing factors of menopause-related endothelial dysfunction, atherosclerosis, hypertension, cardiovascular, and renal diseases.

Impaired vascular function due to ROS could be normalized by natural estrogen therapy, as found in women and animal models of menopause. Moreover, following the estrogens deprivation, oxidative stress increases significantly. Serum concentrations of inflammatory cytokines and pro-oxidant biomarkers were found to be higher in postmenopausal than in premenopausal women. The elevation of cytokines and pro-oxidant markers suggests that there is a high degree of oxidative stress in the postmenopausal state.


Cardiovascular diseases represent the
leading causes of morbidity and
mortality in women after menopause
and 56% of all causes of death in
Western European countries.


One of the major sources of ROS production in cells is a family of membrane-associated enzymatic complexes called nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). The activation of nicotinamide adenine dinucleotide phosphate (NAPDH), a major source of ROS, is often associated with high levels of fatty acids, cholesterol, glucose, or advanced glycation end products (AGEs), all linked to the menopausal state.

Berberine Suppresses ROS Production

Berberine has been reported to suppress NOX isoforms, thereby decreasing ROS production in macrophages and endothelial cells upon inflammatory stimulation.

Berberine Reduces LDL Oxidation

Figure 1. It has been demonstrated that Berberine activates the AMPK cascade, which is involved in the betterment of cardiovascular disorders, type 2 diabetes, and metabolic syndrome.
LEM1505BerberineFig1_274.gif
(click on thumbnail for full sized image)

In endothelial cells, Berberine reduces LDL oxidation induced by ROS and reduces mitochondrial collapse. It also reduces vesicular structures found in patients with vascular diseases that serve as surrogate markers of endothelial dysfunction.

Metformin — a drug used for diabetes, which also offers life extension potential — may exert its cardiovascular protective function through NOX inhibition. (See “Berberine is Superior to Metformin” in the July 2011 issue and “Is Metformin the Metabolic Holy Grail?” In the October 2013 issue). This involves the AMPK pathway — which plays a key role as a master regulator of cellular energy homeostasis. The AMPK pathway is activated by Berberine. Thus, Berberine may play a pivotal role in mediating the AMPK pathway’s antioxidant activity (see Fig. 1).

Berberine improves palmitate-induced endothelial dysfunction by upregulating eNOS — the endothelial-derived nitric oxide synthase, which is necessary to catalyze the production of nitric oxide (NO) from L-arginine and downregulating an isoform of NOX through the activation of AMPK.

Berberine enhances eNOS phosphorylation and reduces the high glucose-induced generation of ROS, cellular apoptosis, NF-κB activation, and expression of adhesion molecules through AMPK signaling cascade activation, a key event in preventing oxidative and inflammatory signaling.

Besides the downregulation of NADPH oxidase and increasing NO production, AMPK activation has been linked to upregulation of the antioxidant enzyme superoxide dismutase (SOD), which helps protect against hydrogen peroxide. An increased SOD expression in Berberine treated diabetic mice was observed in one study.


Menopause results in a subsequent
decrease in life quality affecting
every woman differently.


Glutathione (GSH) is another antioxidant enzyme, which helps to maintain the balance of redox state in organisms. Glutathione is a substrate of glutathione peroxidase (GSH-Px) in the clearance of peroxides. Berberine treatment promotes the production of glutathione peroxidase (an important made-in-the-body antioxidant) and hyperactivates SOD in the liver of mice, lessens induced ROS production, and increases the detoxifying enzymes GSH-Px and SOD in motor neuron-like cells.

Role of Berberine in Cardiovascular Disease Risk

Menopause-related cardiovascular disease risk is associated with decreased ovarian function, in part due to arterial dysfunction and a less favorable blood lipid profile. Hormone replacement with estrogen and progesterone has been shown to reduce plasma concentrations of LDL cholesterol and increase concentrations of HDL cholesterol. High levels of LDL and its oxidized counterpart represent a major risk factor for endothelial dysfunction and atherosclerosis.

Inactivity of the LDL receptor (LDLR) or its low-level expression initiates accumulation of LDL in blood vessels. Alternatively, the receptor of oxidized LDL (oxLDL activates a proatherogenic cascade by inducing endothelial dysfunction, smooth muscle cells proliferation, apoptosis, and the transformation of macrophages into foam cells and platelet activation via NF-κB activation.

Berberine Helps with Breast Cancer

If you’re a woman, you know that the most common cancer among women worldwide is breast cancer. Out of this awareness, you know that novel therapeutic agents are needed to treat this disease. The plant-based alkaloid Berberine has potential therapeutic applications for breast cancer, although a better understanding of the genes and cellular pathways regulated by this compound is needed to define the mechanism of its action in cancer treatment.

In a new review, the molecular targets of Berberine in various cancers, particularly breast cancer, are discussed. Berberine was shown to be effective in inhibiting cell proliferation and promoting apoptosis in various cancerous cells. Some signaling pathways affected by Berberine, including the mitogen-activated protein kinase and Wnt/β-catenin pathways, are critical for reducing cellular migration and sensitivity to various growth factors.

The new review discusses recent studies and consider the application of new prospective approaches based on microRNAs and other crucial regulators for use in future studies to define the action of Berberine in cancer. The effects of Berberine on cancer cell survival and proliferation are also outlined, and there is a surprising amount of information and finding showing Berberine’s applicability.

Reference

  1. Jabbarzadeh Kaboli P, Rahmat A, Ismail P, Ling KH. Targets and mechanisms of Berberine, a natural drug with potential to treat cancer with special focus on breast cancer. Eur J Pharmacol. 2014 Oct 5;740:584 – 95.

Berberine Helps Prevent Oxidized LDL

In another report, it has been found that Berberine induces an enzyme that upregulates LDLR and sterol regulatory element-binding proteins. In accordance with previous cited studies, it has been shown that a combination of Berberine with simvastatin increased the LDLR gene expression to a level significantly higher than that in single therapies.

In human macrophage-derived foam cells treated with oxLDL, Berberine inhibits the oxLDL uptake of macrophages and reduces foam cell formation.

It has also been demonstrated that Berberine combined with atorvastatin is more effective in diminishing another LDL receptor that degrades oxLDL expression than atorvastatin alone.

Another paper showed, both in vitro and in vivo, that Berberine reduces leukocyte-endothelium adhesion, which plays a critical initiating role in inflammation.

Lipid Lowering Power of Berberine Clearly Confirmed

Berberine’s lipid-lowering activity — alone or in association with other nutritional ingredients — has been clearly confirmed in a relatively large number of randomized clinical trials, many of which involve a large number of women (usually from 50% to almost 100% of peri- or postmenopausal age).

In a large placebo-controlled, randomized clinical trial, it was reported that short-term consumption of a combined nutraceutical containing isoflavones and Berberine in 120 mildly dyslipidemic postmenopausal women significantly lowered plasma total cholesterol (13.5% ± 0.7 versus 0.2% ± 0.5), LDL cholesterol (12.4% ± 1.5 versus 0.8% ± 0.7), and TG (18.9% ± 2.5 versus 1.3% ± 1.2), improving menopausal symptoms compared with placebo.2


The benefits of Berberine
supplementation include
the reduction of many
menopause-associated
pathologies.


In a subsample of the same study, it is shown that the consumption of isoflavones and Berberine also improved the serum levels of matrix metalloproteinases, known to promote the invasion of inflammatory cells by degrading the extracellular matrix.

The anti-inflammatory effect of Berberine was also confirmed in patients with acute coronary syndrome following percutaneous coronary intervention. Thus, Berberine seems to be a promising preventive treatment in the initial key steps of atherogenesis and plaque formation in the inner linings of arteries.

Role of Berberine in Diabetes Mellitus Type 2

Different studies have shown that the incidence of diabetes is higher among menopausal women. In fact, estrogen influences not only vascular functions but also insulin sensitivity. Diabetes is a chronic disease characterized by hyperglycemia, hyperinsulinemia, and insulin resistance in peripheral tissues, particularly in the liver, muscles, adipocytes, and pancreatic β-cells.

Individuals with insulin resistance have either decreased levels or absence of insulin receptor expression and subsequent hyperglycemia. Oxidative stress participates in the development and progression of diabetes, in which changes of SOD and catalase were noted in diabetic mice.

It has been reported that taking a low dose of combined estrogens and progesterone therapy led to a decreased risk of developing diabetes and to better glucose control in postmenopausal women.

Another study compared the effects of estradiol and genistein treatments on insulin signaling pathway in the cerebral cortex of ovariectomized young and aged female rats. They observed that aging decreases the translocation of the insulin dependent glucose transporter-4 (GLUT4) and 17β-estradiol, but not genistein, which favors GLUT4 translocation.

Berberine exhibited a high hypoglycemic potential; it has been shown that Berberine activates AMPK with subsequent induction of glycolysis (see Fig. 1). AMPK as an intracellular energy receptor has attracted more attention and become a new target for the treatment of diabetes and its cardiovascular complications due to its regulatory effect on endothelial cell function and energy homeostasis.

In a myoblast cell line treated with insulin to induce insulin resistance, Berberine decreased the reduction in glucose consumption and glucose uptake, at least in part via stimulation of AMPK activity. Berberine enhanced acute insulin-mediated GLUT4 translocation and glucose transport in insulin-resistant myotubes (developing skeletal muscle fibers with a tubular appearance) through activation of the AMPK and PI3K pathways.

Besides the role in AMPK signaling, another paper showed that Berberine increased insulin receptor messenger RNA and protein expression in a variety of human cell lines and hepatitis B virus transfected human liver cells. In a clinical study, the same group observed that Berberine significantly lowered fasting blood glucose, hemoglobin A1c, triglycerides, and insulin levels in patients with diabetes to the same degree as metformin and rosiglitazone (a combination commonly used for diabetes therapy); the percentages of peripheral blood lymphocytes expressing InsR were significantly elevated after therapy.

Berberine exhibited similar hypoglycemic potential as glibenclamide (an anti-diabetes drug that stimulates the release of insulin) to lower area under the curve of the fasting blood glucose in the kidney, liver, and brain of mice with diabetes. The dose-dependent antidiabetic properties of Berberine have been clearly confirmed in a relatively large number of randomized clinical trials, involving a large number of women (usually 50%, almost all in peri- or postmenopausal age). Thus, on the basis of the available evidence, we can reasonably conclude that Berberine could be an ideal supplementation for diabetes.


Berberine improves palmitate-
induced endothelial dysfunction by
upregulating eNOS — the endothelial-
derived nitric oxide synthase, which
is necessary to catalyze the
production of nitric oxide (NO)
from arginine.


Role of Berberine in Depressive Disorder

During the menopausal transition, between 15% and 50% of women experience depressive symptoms; in 15% to 30% of perimenopausal women, they are severe enough to be regarded as a depressive disorder. Fluctuations in gonadal hormone levels are thought to contribute to these depressive conditions, and hormone therapy is commonly used to alleviate climacteric symptoms. Acombination of interactions between neurotransmitters, neuropeptides, oxidative and nitrosative stress, and cytokines are thought to take part in the pathogenesis of depression.

Berberine for Quicker Antidepressant Response

It is theorized that the additive effect of enhancing neurotransmission in three monoamine systems (serotonin, norepinephrine, and dopamine) may lead to improved efficacy and quicker onset of antidepressant responses. Clinical studies have reported that patients with depression presented also with oxidative disturbances such as elevated lipid peroxidation products and reduced levels of SOD. NF-κB activity is regulated at least in part by the intensity of intracellular oxidative and nitrosative stress and, in turn, controls the regulation of genes encoding proteins involved in immune and inflammatory responses.

Depressed patients often display enhanced cytokine levels including interleukin-6 (IL-6), C-reactive protein, interleukin-1-beta (IL-1β), and TNFα; they can enter the brain and may cause alterations of the metabolism of serotonin and dopamine. Thus these studies showed a correlation between oxidative and nitrosative stress, increased levels of cytokines, and altered levels of biogenic amines. Mechanistically, estrogen plays an important role in mood and cognitive regulation. It is reported that monoamine oxidase-A (MAO-A) total distribution volume, an index of MAO-A density, is elevated in perimenopausal women.

Berberine inhibited the immobility period in mice in both forced swim and tail-suspension test, two animal models of depression, in a dose independent manner. Among the reported bioactivities of Berberine is the inhibition of MAO-A enzyme activity.

Berberine Increases Norepinephrine, Serotonin, and Dopamine Levels

In fact, the acute and chronic administration of Berberine in mice resulted in increased levels of norepinephrine, serotonin, and dopamine, neurotransmitters induced by a MAO-A enzyme. In accordance with another study, this study showed the protective antidepressant-like effect of Berberine against biogenic amine depletion (a monoamine depletor is commonly used to induce depression in animals) and against oxidative nitrosative stress-mediated inflammatory cascade and apoptotic signaling pathway in rats.

Recently, the important role of endoplasmic reticulum protein sigma-1 receptors (sigma receptors) in the modulation of various neurotransmitters has been identified. These receptors seem to be a promising target for the pathophysiology of neuropsychiatric disorders, in particular for depression. Sigma-1 receptor modulators are considered the drugs of the future for the treatment of major depression and anxiety. It is reported that Berberine has an effect on sigma receptor-1 similar to many synthetic antidepressant drugs. However, at the best of our knowledge, there are no available data on the evaluation of the potential antidepressant effects of Berberine in humans.

Summary

Standard doses of Berberine are usually well-tolerated and adverse reactions are rare. As perimenopause set in, the reduction in the estrogen levels are connected with the onslaught of discomforts and pathologies, which strongly affects the quality of life for many women. However, there is growing evidence that Berberine can minimize the negative consequences resulting from low estrogens levels, and do this without the undesirable side effects that are commonly associated with hormone replacement therapy. In all likelihood, it seems as though Berberine might be an important, safe and efficient nutritional supplement to sustain women during the menopausal transition.

References

  1. Caliceti C, Rizzo P, Cicero AF. Potential Benefits of Berberine in the Management of Perimenopausal Syndrome. Oxid Med Cell Longev. 2015;2015:723093. Epub 2015 Feb 17.
  2. Cianci A, Cicero AF, Colacurci N, Matarazzo MG, De Leo V. Activity of isoflavones and berberine on vasomotor symptoms and lipid profile in menopausal women. Gynecol Endocrinol. 2012 Sep;28(9):699 – 702.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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