Nutrition in Menopause: Scientific Basis and Recommendations

Rakesh Sharma,

1Innovations And Solutions USA and Florida State University, Tallahassee 32304

rksz2009@gmail.com; Phone: 011-91-9548336632

Abstract
Women in their late forties or early fifties experience stop of menstrual cycle and menstrual flow
mixed with emotional and physical changes years before or after menopause as a result of reduced
estrogen. Over past years, estrogen replacement therapy has caused concerns of high risk of breast
cancer and uterine fibroids. Nutrition, dietary supplementation and alternative therapy have
played a vital role to avoid risk of cancer and show relief in postmenopausal symptoms to make
women feel better. Nutrition and food supplements are available at nonprescription counters and
their self-prescription has increased at a large scale. The current literature suggests the use of
food, diet, nutrition supplements in reducing menopause symptoms and postmenoapausal risk
management. In present chapter, a glimpse of menopause, risks of osteoporosis-cancer-weight
loss-diabetes, with a mechanistic and scientific basis of nutrition, diet and nutraceutical
formulation in menopause is presented with recent recommendations of food supplements in
reducing menopausal symptoms and risk management. A detailed account is presented on
mechanism of lignans and isoflavones in osteoporosis, arthritis, and atherosclerosis in menopausal
women with present scenario and recommended guidelines of nutrition in menopause as hand-
book notes.

Key Words: Menopause, Osteoporosis, Food and supplements, Menoapuse Nutraceutical

Formula
Introduction

The elderly men and elderly women over 60 years constitute approximately one third of total
population, with more than 45 million man and 40 million postmenopausal women in US [Cunha-
Henriques et al. 2011]. Over the past several years, clinical trials have proven that cholesterol
lowering diets and nutrition therapy reduce the risk of menopause and osteoporosis among elderly
woman with the fact that drugs show side effects [Canonico et al.2011]. With demographic shift
of over aged women population at rise, more number of younger women will be afflicted with
menopause, cardiovascular disease and osteoporosis; and a search for potential therapies for
menopause and osteoporosis will be needed [Canonico et al.2011]. The anabolic agent 17β
Estradiol (17β-E) is approved by FDA for the treatment of menopause. In elderly women, 17β
Estradiol has been shown to reduce the menopause symptoms and osteoporosis management after
one year treatment. However, daily compliance is inconvenient and expansive with risks of breast
and uterine cancer in long term treated women. Such concern necessitated for experimental
search of cheap, easily available, risk free, natural sources of nurtraceutical abundant in bioactive
foods. Present day, menopause preventive nutrition supplements have been approved such as
isoflavones in soy products, secoisolariciresinol from flax seeds and others [Prasad et al.
1997,1999, 2000a and 2000b, Schottner et al.1998]. However, such nutrition treatments remain
widely popular bioactive foods in menopause prevention for reducing symptoms of hot flash and
risk of osteoporosis without less or no curative effects of bring back hormones to normal.

The concept of bioactive foods was initially considered as natural foods to provide energy as
recommended daily requirement in the body for health till year 1990. Later the importance of
nutrition was realized as beneficial in menopausal disorders with growing use of the
nutraceuticals, bioactive foods and dietary supplements as self-prescription in postmenopausal
conditions significantly in the last decade. In new era of 21st century showed enormous growing
awareness of nutrition in elderly women health. In general, potent naturopathic therapeutic
supplements with accepted concept of nutraceutical medicine emerged as new branch of
‘complementary and alternative medicine’(CAM). In last nine years, national and federal bodies
accepted nutrition, bioactive foods and nutraceuticals as possible nutraceutical therapy in main
stream of medical education and health. The healthcare industry demonstrated the shift of
growing population from medical treatment of menopause (due to high risk of breast and uterine
cancers by hormone medication) towards non-prescription herbs, nutraceuticals and bioactive
foods as self-medication in reducing menaopause symptoms and prevention. The growing
awareness of nutraceutical benefits and shift of healthcare economics in favor of nutraceuticals
brought naturopathic medicine in spotlight of government health policy on systematic use of
bioactive foods and nutraceuticals in prevention and control of menopause.

The major efforts were devoted in investigation of stimulating effect on estrogen and
progesterone maintenance during late forties or early fifties and inhibitory effect on cell
proliferation, cancer oncogenesis to result the reduced metastasis, delayed apoptosis, reduced
necrosis and rate of malignancy growth in initial stages. In last two years the use of nutraceuticals
and bioactive foods in prevention and menopause control has been extended further as protective
nutrition supplementation policy of at various elderly women rehabilitation centers under their
independent supervision. However, origin of menopausal symptoms and mechanism of cancer
development is still remain unproven and unvalidated but practice of nutraceuticals as food
supplements in reducing menopausal symptoms and cancer prevention is acceptable.

What are bioactive foods and nutraceuticals?

Whole fresh foods are available as organic foods. At any organic food store, food extracts and
prebiotic or probiotic preparations available as ‘bioactive foods’ and nutraceuticals are natural
food supplements. Natural food supplements have value in health promoting, disease prevention
or semi-medicinal properties. Bioactive foods are found as natural products from (a) the food
industry, (b) the herbal and dietary supplement, (c) pharmaceutical industry, and (d) the newly
emerged bioengineered microorganisms, agroproducts or active biomolecules. It may range from
isolated nutrients, herbal products, dietary supplements and diets to genetically engineered
“custom” foods and processed products such as cereals, soups and beverages. Chemically the
nutraceuticals may be classified as isoprenoid derivatives (terpenoids, carotenoids, saponins,
tocotrienols, tocopherols, terpenes), phenolic compounds (couramines, tannins, ligrins,
anthrocynins, isoflavones, flavonones, flavanoids), carbohydrate derivatives (ascorbic acid,
oligosaccharides, non-starch PS), fatty acid and structural lipids (n-3 PUFA, CLA, MUFA,
sphingolipids, lecithins), amino acid derivatives (amino acids, allyl-S compounds, capsaicnoids,
isothiocyanates, indols, folate, choline), microbes (probiotics, prebiotics) and minerals ( Ca, Zn,
Cu, K, Se) [Sharma 2009]. For menopause prevention, phytoesterogens mainly lignans from soy,
secoisolariciresinol from flax seeds, red clover, black cohosh, vitex, Sanguinaria, ginseng, don
qui are significant as shown in Table 1.

Table 1. Nutrient supplements, fruits and nutraceuticals for menopause prevention

Food Main chemical constituent Mechanism of action

Soy isoflavones stimulating estrogens/estriol

Black Cohosh tumoricidal effects
Ginseng ginsenosides HbA1c, endocrine effects,
neuro-, cardio-,anticancer
Flax seeds secoisolariciresinol estrogen/estradiol metabolism
aromatase inhibition
Vitex kaempferol, quercetagetin progesterone/testosterone synthesis
premenstrual Dysphoric Disorder
more fertility,pro-apoptotic caspase
Red clover PMS,menopausal symptoms
Sanguinaria caustic phytosterol anticancer, berberine effect
Sabine PMS, menopausal symptoms
Garlic Allylic sulfides anticancer, Anticholestrol
Carrots, orange vegetable Catrotenoids Antioxidant
Fruits/Green tea Flavanoids Antioxidants
Soy foods Isoflavones Anticancer
Cruiciferous vegetables Isothiocynates DNA protection
Citrus fruits Limonene Excretion of carcinogens

Bioactive foods, organic foods and nutraceutical supplements play very significant role in supply
of energy and maintaining natural hormonal balance during decline of estrogen and progesterone
production in late forties and beyond to meet the demand of menopause.

What is Menopause?
Menopause (called mee-na-paaz) is the time, when monthly release of eggs by a woman’s
ovaries ends, menstruation ceases, and she is no longer able to conceive child due to a decline in
production of the hormone estrogen. Biological mechanisms of menopause begin years before,
and symptoms continue several years afterward. Initially it may be missed one or two periods
followed by heavy vaginal bleeding is called ‘perimenopause’ followed by symptoms of
‘menopause’. Menopause syndrome is a state of changes in body during late forties or early
fifties, manifested with depression, hot flashes, lack of libido, cognitive disturbance, skin and
vaginal dryness, osteoporosis, stress, PMS and heart disease.

For ‘hot flashes’ due to menopause, FDA recommends estrogen replacement therapy (ERT) up to
10 milligrams of natural progesterone one per two ounce jar of synthetic progestins or
progesterone preparations including phytoprogesterones and phytoesterogens as one-half tea
spoon a day from day 7-day 20 (period of ovulation); then full one tea spoonful twice a day from
day 21 to the start of the menstruation period. However, ERT increases the risk of breast cancer.
After menopause, woman becomes at increased risk for a number of diseases, notably obesity,
heart disease, muscle loss and osteoporosis, against which estrogen offers great protection during
her reproductive years. However, status of hormone replacement therapy in protection is
controversial because both estrogen and progesterone prolonged treatment show an increased risk
of fibroids, breast and uterine cancer [Sablik et al.2008, Seeger et al. 2008].

Biochemical Basis of Menopause

From biochemistry standpoint, testosterone, esterogen and progesterone are main sex hormones
while major hormone producing glands are ovaries, under control of hypothalamus, pituitary
gland. However, other glands do play a supportive role such as secretions from thymus, thyroid,
adrenal and pancreas glands.

Cholesterol is converted into steroid hormones (cortisol, aldosterone and cortisone) to produce
androgen(testosterone) and estrogens (estradiol, estrone and estriol). Estrogens get coverted into
progestins(progestens, progestogens) to make natural progesterone. However, cholesterol product
pregnenolone also converts into DHEA while ovaries also produce DHEA to make estradiol,
testosterone and progesterone under hormonal control of hypothalamus (Gonadotropin releasing
hormone or GNRH) and pitutary gland (leutinizing hormone and follicle stimulating hormone).
Both estrogen and progesterone show feedback effect on hypothalamus and pituitary gland
control on hormonal production in ovaries [Lonning et al.1995].

The ovaries produce the majority of estrogens circulating within premenopausal women, while
that circulating in postmenopausal women arises from peripheral tissues (fat, liver, and muscle)
"aromatizing" androgen hormones (derived from both the adrenal glands and ovaries) into
estrogens. However, aromatase enzymes also form estrogens in fat cells and breast tissues outside
ovaries.

Glucose  Acetyl-CoA  Mevalonate  HMG CoA

HMG CoA Reductase
Diet Squalene
Supplements Squalene Epoxidase
Nutraceutical Cholesterol
s Cholesterol 7 Hydroxylase
Estradiol Estrone DHEAPregnanolone

Testosterone Cortisol Prgesterone

Figure 1: A sketch is proposed on formation of estrones and estrogens from cholesterol (on left) and source of
cholesterol and esterogen synthesis in cell(on right). Structural formula of a lignin secoisolariciresorsinol diglucoside
at bottom on right.

The "breakdown" or catabolism of estrogens within the female body is far more complex than
simple excretion through the kidneys or intestinal tract. Estrogens are broken down by
hydroxylation reactions, wherein they can enter a number of different paths (see Figure 1).
Estradiol, the most potent estrogen produced in women, can enter 2-, 4-, or 16- hydroxylation
pathways, giving rise to 2-hydroxy-, 4- hydroxy-, and 16-hydroxy-compounds, respectively. The
2- and 4-hydroxy metabolites (called catechol estrogens) can be inactivated by an enzyme called
COMT (catechol O-methyl transferase), which uses S-adenosylmethionine (SAMe) to perform a
methylation step (addition of a chemical methyl group). If this methylation step is incomplete,
these catechol estrogens are oxidized to other chemically reactive compounds. The 4-
hydroxyestrone and 16-hydroxyestradiol forms retain estrogenic properties and are considered to
be carcinogenic . The 16-hydroxy product does not appear to be acted upon by any deactivating
enzymes. The 2- hydroxylation pathway can be viewed as anti-carcinogenic while the 16-
hydroxylation pathway can be viewed as pro-carcinogenic. This estrogen metabolism "balancing
act" (See Figure 1) points to women whose estrogen metabolism is preferential to the 16-
hydroxylation pathway possibly being at higher risk for breast cancer[Bradlow et al. 1996].

Physiochemical facts of Menopause

In the absence of effective FDA regulation, meat industry uses animal feed additives,
antibiotics, tranquilizers, pesticides, drugs, flavors, industrial wastes and growth hormones. Most
of them toxic or carcinogenic such as diethylstilbesterol as growth promoting animal feed.
Several facts have surfaced in this regard:

 Aldosterone hormone controls the potassium retention and sodium removal

 Dehydroepiandrosterone or DHEA may synthesize estrogens
 After menopause, adrenal cortex in adrenal glands maintain androgens and ovaries curtail
or stimulate slow the estrogen levels under control of hypothalamus and pituitary glands
with manifestations of depression, sweating, vaginal dryness, libido loss, sleepless nights
and hot flashes
 Hypothalamus is controlled by nerve signals. It sends chemical message or gonadotropin
releasing hormone to pituitary gland to stimulate ovary to release luteinizing hormone and
follicle stimulating hormone in the process of follicle development and esterogen
production
 Prostaglandins act as uterine muscle stimulators to cause uterine contraction
 Calcitonin and vasopressin control the bone mineralization balanced by dietary intake and
excretion from kidneys and intestine as shown in Figure 2
 Decreased conversion of estrogen and progesterone from cholesterol enhances circulating
cholesterol in blood to cause dyslipidemia, hypertension and atherosclerosis associated
with glucose to cause diabetes along with iodine deficiency may cause hypothyroidism
 Vitamin D3 formation is slows down to cause elevated thermogenic reactions and skin
more porous for hot flashes [Freedman et al.1995]
 Dietary Calcium Osteoblasts/Osteoclast
cells Bone cells Calcitonin

Extrace Parathormone
-llular
fluid Vitamin D3

Feces Kidney
Urine

Figure 2: Bone physiology in menopause. Calcium and phosphorus support synthesis of calcium hydroxyapatite and
the mineral transport in osteoclasts and osteoblasts underregulation of calcitonin, parathormone and vitamin D3.

Risk of Osteoporosis in Menopause

After age in forties, women lose 500 mg of calcium from bones every day and plasma calcium is
kept in balance by bone metabolism [Saito et al.1994]. Elderly women face a 17.5% life time risk
of hip fracture, costing $45 billion in next ten years [Sji et al.1997, Recker et al.209]. Bone
mineral metabolism is the biochemical mechanism of calcium and phosphate uptake from blood
or hydroxyapatite formation deposited in bone daily in cells called osteoblasts. Other cells called
osteoclasts keep balance of calcium phosphorus by removing them from bone if they exceed over
normal level in bone. Thus both osteoblasts and osteoclasts bone cells maintain balance of
calcium and phosphorus between dietary intake and intestinal digestion or renal excretion leaving
balance in extracellular fluid in exchange with intracellular calcium and phosphorus in cells as
shown in Figure 2. In menopause, due to less estrogen, androgen, osteoblasts slow down
hydroxyapatite formation under the effect of calcium regulating hormone calcitonin and other
vasopressin hormone [Ohnaka et al. 2009]. Other factors are calcium malabsorption, high
phosphorus intake, magnesium sulfate [Aydin et al. 2010], drugs, salt intake, physical activity
etc.[Anderson et al. 1996]. Major risks of bone health in menopause is age dependent
osteoporosis [Chailurkit et al. 2002, Sowers et al. 2000], and decreased bone density at the rate of
1 million fractures every year attributable to osteoporosis [Yilmez et al.2009, Pal et al. 2008].
Several facts have emerged in menopause as following:
 One in every six white specially short stature women have hip fracture in life time
 Reduced bone mass with age is high among alcoholics after age sixty
 Pecos Indians have less cadmium and high lead concentrations in bones
 Decreased natural progesterone slows down osteoblasts in bone growth while other sex
steroids
 Chronic bronchitis, loss of self-esteem, productivity, acidosis, low spine bone mineral
density, low body weight, small vertebrae in women are risks of osteoporosis
  Serum OPG, RANKL, osteoprotegerin, NFK-B recptor activator [Marini et al.2008, Liu et
al.2004,2005]
Dietary calcium & Sunlight exposure
Phosphorus dietary vitamin D3

Blood Liver
(Osteoblasts)

CALCITONIN
PARATHORMONE
(Osteoclasts) Renin-angiotensin

Figure 3: Calcium Phosphorus metabolism and hormonal regulation

Risks of Atherosclerosis and Obesity in Menopause

The health consequences of atherosclerosis among elderly women in menopause are costing all
Americans over $25 billions annually now and it is projected to exceed $ 75 billion by the year
2020 [Pasternak et al. 2002]. The elderly men and elderly women over 60 years constitute
approximately one third of total population, with more than 45 million man and 40 million
postmenopausal women in US [Cunha-Henriques et al. 2011]. By the end of next decade,
approximately one in every three American will be 65 years of age or older, while the number of
people aged 85 or older will double during this period [Pasternak et al.2002, Heart statistics
update 2003]. With demographic shift of over aged population at rise, more number of women in
menopause will be afflicted with hypertension, cardiovascular disease and atherosclerosis
[Sharma et al.2010] and search for potential therapies for atherosclerosis and CVD will be
needed. The prevalence of age related CVS and atherosclerosis is greater in women than in men
[Sharma et al.2010a]. It is estimated that severe dyslipidemia or increased serum lipids
(cholesterol, triglycerides, LDL-cholesterol lipids) results with atherosclerosis in 25-30% aging
women [Sharma et al. 2010a]. In United States, a conservative estimate is that nearly half of all
men and women over age 50 years will suffer from atherosclerosis with other complications such
as obesity stroke, renal complications and osteoporosis resulting in more than 2.5 million total
secondary cardiac disorders or risks [Compston et al.2011].
With aging in women, cholesterol conversion to androgens and estrogens gets slow in the
body [Bednarek-Tupikowska et al. 2008]. It induces dyslipidemia, high serum lipids, blood
pressure, slow arteriosis and plaque formation. To keep balance in this process, due to feedback
negative effect on cholesterol synthesis, ratio hydroxymethylglutaryl-CoA Reductase (HMG-
CoA-R) : Cholesterol 7α Hydroxylase is decreased. It can be ascribed as rate limiting step of
mevalonate conversion to HMG-CoA synthesis is decreased to synthesize squalene while
squalene epoxidase slows down the synthesize of new cholesterol. Enhanced cholesterol
breakdown by cholesterol 7α hydroxylase to form different steroids and lipids also enhances as
shown in Figure 4. As a result, such feedback effect also induces elevated glucose and
cholesterol circulating in blood to put women at the risk of diabetes and atherosclerosis in
menopause. The anabolic agent 17β Estradiol (17β-E) is approved by FDA for the treatment of
atherosclerosis in elderly women. Both statins, 17β-Estradiol drugs have been shown to increase
cholesterol desaturation and dyslipidemia management after one year of treatment. However,
daily compliance is inconvenient and expansive with increased risk of breast cancer. It limits the
use of statins and 17β-Estradiol to elderly women with severe atherosclerosis or who show
uncontrolled dyslipidemia management and carbohydrate deficient transferrin [Leusink wrt al.
2000]. It warrants further exploration of alternatives and/or adjunctive approaches of dietary
supplements, nutraceuticals and foods that can produce clinically relevant lipid sparing effects
[Prasad 2010]. With technical advances, early detection of slow disease progress in menopause is
now high priority of risk assessment such as time series of heart function evaluation and
cardiovascular wall remodeling tests by:
 early molecular markers [Sharma et al. 2010b ]
 stimulation of chemotaxic activity, proliferation, and differentiation in cells of smooth
muscle cells in carotid and coronary arteries [Pensumathsa et al. 2007, Prasad, 2009]
 protection of smooth muscle cells from apoptosis [Dupasquier et al.2007]
 decrease in plaque size as observed by histopathology and biomarkers [Sharma et al.2009]
 differentiation in vitro, thrombus phenotypic markers such as accumulation of collagenous
matrix; expression of biomarker matalloprotease (MMP) enzyme activity;
 secretion of inflammatory proteins, marker proteins of cardiovascular differentiation; and
precipitation of calcium, lipid deposition and thrombus formation in form of plaques
embedded in walls
 How does dietary supplement act on lipid
metabolism to make cholesterol lowering
effect in arteries? Combined effect reduces
events of atherosclerosis in the arteries.

Figure 4: Metabolism of lipids in atherosclerosis.

Source: http://www.scribd.com/ doc/76555640/Statins-What-We-Need-To-Know-On-Statins

Risk of cancer in menopause

Risk of endometrial cancer and breast cancer are elevated two to three fold by tamoxifen use
among postmenopausal women [Lee et al. 2011, Regan et al.2011]. Moreover, vasomotor
symptoms ("hot flashes") and thromboembolic events (stroke, pulmonary embolism, or deep vein
thrombosis, similar to risks also accompany its use[Bernstein et al.1999]. Primary risk for
developing breast cancer by age 40 is 0.5%, climbing to 10% by age 60-as well as lifetime
exposure to "unopposed" estrogens (early menarche, late menopause, late first pregnancy, or
prolonged use of estrogen-based oral contraceptives), the number of breast biopsies experienced,
and atypical hyperplasia determined in a breast biopsy[McPherson et al.2000]. Gail model was
developed for women who have already sustained one breast cancer and experience an increased
risk for a second primary tumor[Gail et al 2001]. The model highlighted the breast cancer
susceptibility (BCS) genes and genetic mutations. BCS genes code for large proteins involved in
DNA repair and the integrity of genes or DNA. Mutations of the BCS genes BRCA1 and BRCA2
(and CHEK2) account for only 15-20% of breast cancer within families and less than 5% of
breast cancer overall[Meijers-Heijboer et al.2002, Nathanson et al.2001]. These mutations
manifest as either a loss of control on cell division, cell death, or the lifespan of cells, fostering
the growth of cancer cells, or a loss of gene stability to disrupt BCS genes[Clemons et al.2001].
However, increasing research focus on genetic factors or genetic link as woman's risk for
developing breast cancer remains uncovered in majority of women in the U.S. population. Current
research points to a genetically-determined increased risk among only 10-15% of women that
develop breast cancer. Remaining 85-90% of women who develop breast cancer from other
"external" factors (dietary free radicals, no physical activity, estrogen-containing medications)
without genetic link do have an opportunity to adopt a preemptive food supplementation strategy
to reduce their cancer risk by using safe, effective, and well tolerated breast cancer preventive
food supplements. Of specific mention, a lignan secoisolariciresinol diglucoside (SDG) is
marketed as Brevail®, product from North American flaxseed (Linum usitatissimum). Other
sources of SDG are garlic, broccoli, asparagus, dried apricots and prunes. In menopause,
hormonal risk factors are likely to modulate genetic predisposition to breast cancer such as
estrogen treatment by ERT induces initiation and the promotion of breast cancer or removal of
ovaries shows a potent therapeutic effect in breast cancer[Beaton et al.1896] Lifestyle strategies
provide greater insulation against the risk of cancer.

Scientific Basis of Food supplementation in menopause

Food supplements and nutraceuticals may act as essential nutrient, as drug like, as regulatory
biochemical metabolite and as phytohormone in the body. Recently, some prominent evidences
are reported in favor of cancer inhibitory metabolic activity of nutraceuticals in the human body:

 Slow growing symptoms are high blood pressure osteoporosis, schizophrenia like
symptoms, weight gain, B6 deficiency induced carpal-tunnel syndrome
 High intake of dietary fiber, vitamin C, beta-carotene, raspberry leaves, marjoram, thyme
teas, vitamin B6 reduce postmenstrual edema
 Intake of phytosterogen containing foods such as isoflavones in soy beans help to block
esterogen from entering esterogen receptor sites or filling the gap of esterogen to stop hot
flashes in women
 Vitamin C with E supplementation stimulates esterogen production and reduce hot flashes
 Calcium and phosphorus metabolisms in bones are controlled by a balance between
osteoclast and osteoblast activities under control of calcitonin and parathormone. Basic
principle of bone health in menopause is that bone density improves with dietary
progesterone stimulators from legume leaves, cow’s milk, aloe vera, almond oil,
safflower, avocado, jojoba instead of synthetic progestin, medroxyprogesterone with
estradiol

 Goals of food supplementation in menopause:

A good account is available in recent studies on diet, nutrition knowledge and health status of
menopause in women [Rivlin et al. 2007, Pons et al. 2006, Daley et al. 2006, Karacam et al. 2007,
Barr et al. 2000]. Ideal goals of food supplementation are:

 Good regulator of entire endocrine system

 Good regulator of accessory organs such as alfalfa, parsley, dandelion greens, chard
vegetables
 Keeping low LDL cholesterol and its precursor
 Keeping calcium-phosphorus positive metabolic balance with enough vitamin A,K,D3,
folic acid and low phosphorus intake from cheese, processed meats, baked products,
cola, soups, puddings, toppings, bread, cereals, potatoes, phosphorus additives
 Improving estrogen and progesterone positive balance
 Keeping low dairy products, meat and no junk foods, soda, coffee, apple juice
 Keep low aluminum through antacids
 Grow your sprouted seeds

How phytoestrogens act?

Over years, experimental studies have explored major breakthroughs to get success in protective
effects of phytoesterogen rich food supplements on menopause in elderly women. Most of
evidences have accrued from animal studies or mouth spoken testimonies in support of protective
effects of foods and supplements in menopause. In next section, I describe the mechanism of
action for phytoestrogens.
The mechanisms by which phytoestrogens exert their beneficial effects on diabetes and obesity
are still unclear. Phytoestrogens have structural similarities to endogenous estrogens.
Phytoestrogens act as weak estrogens and compete with 17ß-estradiol for binding to the
intranuclear estrogen receptor protein to modulate gene transcription. At least 2 distinct estrogen
receptors (estrogen receptor and estrogen receptor ß) have been described and found to be
expressed in adipose tissue. Phytoestrogens bind to both estrogen receptors but bind more
strongly to estrogen receptor ß. Phytoestrogens also exert their biological effects via non-estrogen
receptor-mediated mechanisms by inhibition of tyrosine kinases, DNA topoisomerase I (EC
5.99.1.2) and DNA topoisomerase II (EC 5.99.1.3) and ribosomal S6 kinase, involved in cell-
signaling mechanisms and nuclear events such as cell proliferation and differentiation.
Phytoestrogens have potent antioxidative activity. Some of the cellular and metabolic effects of
soy (isoflavones) and flaxseed (lignans) may be through both estrogen receptor– and non-estrogen
receptor–mediated mechanisms in obesity and diabetes. Several experimental studies support the
mechanism of phytoesterogens in glucose homeostasis, insulin secretion, and lipid metabolism in
menopause (see Table 4).
 Soybean isoflavones such as genistein and daidzein inhibited glucose uptake into rabbit
intestinal brush border membrane vesicles in a dose-dependent manner to protect against
glucose-induced oxidation of human LDL [Verhoeven et al.1999].
 In intestinal glucose absorption in vivo, intestinal sodium-dependent glucose transporter 1
and facilitated glucose transporter 2 increased in experimental diabetes to result
postprandial hyperglycemia [Fedorak et al. 1991, Burant et al. 1994].
 protein tyrosine kinases play a permissive role in the regulation of insulin secretion from
pancreatic ß cells. Isoflavone genistein as a protein tyrosine kinase inhibitor exerts
multiple actions on insulin release from pancreatic islet cells [Hisatomi et al.1997].
Genistein inhibited islet tyrosine kinase activities and glucose- and sulfonylurea-
stimulated insulin release without affecting glucose metabolism [Szkudelska et al.2000].
 Genistein inhibits glucose-stimulated insulin secretion [Persaud et al.1999]. Genistein
appears to have direct effects on lipid metabolism in liver and adipose tissue by affecting
both lipogenesis and lipolysis
 Daidzein, increases insulin secretion from mouse islets independent of tyrosine kinase
[Sorenson et al.1994].
 Genistein reduced the incorporation of [14C]glucose into lipids and increased the output of
fatty acids into the medium [Nogowski et al.1998]. These changes were accompanied by a
decrease in hepatic triacylglycerol content.
 Genistein decrease the number of high-affinity insulin receptors in the livers and
adipocytes of ovariectomized rats to decrease glucose conversion to lipids independent of
insulin [Mackowiak et al. 1999].
 Genistein (0.1 and 1 mmol/L) augmented basal lipolysis, and at the lowest concentration
(0.01) it increased lipolysis in adipocytes stimulated by epinephrine, insulin independent
of insulin-stimulated pyruvate dehydrogenase (EC 1.2.4.1) or glycogen synthase (EC
2.4.1.11) [Abler et al.1992]
 Genistein inhibited de novo lipid synthesis from acetate and glucose but stimulated
lipolysis [Persaud et al.1999].
 Genistein inhibited glucose uptake stimulated by uncoupling protein 3 in skeletal muscle
cells [Huppertz et al.2001]
 Coumestrol decreased muscle glycogen, insulin binding with membrane via changes in
insulin receptors in ovariectomized rats (Nogowski et al 1992].
 Coumestrol decreased plasma cholesterol concentrations in a dose-dependent manner
 TABLE 4 . Metabolic effects of phytoestrogens at the cellular level in menopause
--------------------------------------------------------------------------------------------------------------------
Soybean Target Cell Action
--------------------------------------------------------------------------------------------------------------------
Daidzein intestine cells Inhibits glucose uptake into
brush border membrane vesicles
pancreatic cells Islet cell proliferation and inhibits
glucose- and sulfonylurea-stimulated
insulin receptors
Geneistein hepatocytes 1. Decreases incorporation of glucose into lipids and the
number of insulin receptors
2. Inhibits glucose conversion into total lipids, stimulates
basal lipolysis and epinephrine-induced lipolysis, and inhibits
insulin-stimulated glucose oxidation in a dose-dependent
manner but has no effects on insulin’s stimulation of pyruvate
dehydrogenase and glycogen synthase activities or tyrosine
adipocytes autophosphorylation of insulin receptors Inhibits glucose
bones uptake stimulated by uncoupling protein

Coumesterol muscle cells Decreases glycogen and inhibits insulin binding to membranes
--------------------------------------------------------------------------------------------------------------------

Meta-analysis and preclinical studies suggest a mixture of information on less or no benefits

of soy products in diet and isoflavones in menopause [Xiao,.2008; Campbell et al. 2010; Khalil et
al.2002,2005; Arjmandi et al. 2004,2005,2010; Hooshmand et al.2011].

In following sections, I describe here thoroughly investigated mechanisms of flax seed lignans,
soy bean isoflavones, vitamin E and vitamin D3.

I. Mechanism of lignans in menopause

Many reports indicate that approximately two-third of the cases of the cardiovascular disease in
women are associated with risk of primary glomerular disease induced by drug intake of diuretics
and statins, while the remaining one-third cases are caused by menopause, thromboembolism,
hormone replacement therapy, cancer, diabetes mellitus, autoimmune diseases, or amyloidosis
[Heart Statistical Update 2003]. It clearly leaves an option of non-pharmaceutical means to reduce
the breast cancer and cardiovascular risks. Major focus was on understanding the role of
secoisolariciresorsinol diglucoside (SDG) on benefits in cancer prevention, cardiovascular
protection and urinary secretion of estradiol.
 Figure 5:Sequential
changes in serum lipid
concentrations
(triglyceride, LDL-C,
TC/LDL-C, LDL-
C/HDL-C, HDL-C,
VLDL-C, Cholesterol)
in 4 groups of animals.
Results shown as mean
+ SEM at different
times of dietary
intervention.

Flax seed is a very rich source of lignan, linolinic acid, mucilage and secoisolariciresinol
constituents with potential to lower down the blood cholesterol [Touilaud et al.2007]. Flaxseed
was reported to reduce 5-9% total cholesterol after consumption of 40-50 g flax seed to prevent
atherosclerosis [Lucas et al. 2004, 2011]. Prasad et al.(1998, 1999, 2007) evidenced the
prevention of atherosclerotic lesions in hypercholesterolemic rabbits without noticeable
cholesterol lowering effects. Moreover, authors specified also other components of flaxseed
responsible of reducing atherosclerosis. Initial studies on rabbits indicated the importance of
flaxseed lignans in lipid lowering [Prasad 1998], oxidative stress with possible implications on
diabetes [Prasad 2005]. Other group of investigators reported lignans as antithrombotic in elderly
women [Lucas et al. 2004, 2011; Patade et al.2008]. Secoisolariciresinol diglucodide (SDG) was
identified as potent lignan in doses over 2.4 g/kg diet to lower down atherosclerosis by 75% as
shown in Figure 5[Prasad, 2009]. In other studies, Saagar et al. 2009 reported the antiresorptive
effects of flax seeds supplementation in men and women not on any hormonal treatment [Saggar et
al.2009]. Investigators in other study showed supplementation of 7.5 g-22.5 g/kg weight lignan SDG
daily for three months significantly reduced lipids and enhanced HDL [Prasad, 2009].

Present time, flax seed related studies suggest that:

 Flaxseed is beneficial in reducing hypercholesterolemia, aortic fatty streak area and
progression of atherosclerosis lesions in ovarian hormone deficiency in hamster animal
model
 Cardioprotective property of flaxseed was due to its hypercholesterolemic effect including
other possible potential antioxidative, anti-inflammatory, antithrombotic effects
 Inverse relationship of low to high increased flaxseed levels and significantly decreased
plasma cholesterol concentrations
 Flaxseed in diet decrease cholesterol but no effect on esterified cholesterol, total liver
cholesterol but increased TG unlike the immediate effect of esterogen on lipids
  Possibility of active role of atherosclerosis specific gene products including adiponectin,
MMP, CYP11B2, IGF-1 synthesis at tissue level [Jurimae et al. 2009, Prasad,
2000,Sharma et al. 2009, Fukumitsu et al. 2008].
 Flax seed works best in the body when it's taken along with antioxidants, such as vitamins
E, carotene, and other soy nutrients, such as vitamin B6 and magnesium [Lucas et al.2011,
et al.2004].

In last decade, flaxseed was considered as source of hypocholeterolemic and antiatherogenic

agent due to its high content of ALA [An et al.2009, 2004]. Flax seed was reported to lower blood
pressure in dyslipidemic patients [Paschos et al.2007, Recently, SDG was reported effective in
cardioprotection, ischemia reperfusion injury and angiogenesis [Penumathsa et al. 2007].
However, less is known for flaxseed lignan induced gene expression and its mechanism
[Fukumitsu et al.2008]. Flax seed can reduce further atherosclerosis lesion formation by 50-75%
upon supplementation of SDG in rabbits [Penumathsa et al.2007, Campbell et al.2010]. The
results were supported by the fact that increasing diet levels of SDG resulted in lipid lowering,
low blood pressure, remodeling of atherogenic wall in golden hamster model of atherogenesis fed
normal and high SDG with flax seed supplemented diets. To explore molecular mechanism
several morphometric parameters were determined using a direct 3D approach including inner and
outer lumen diameters, plaque volume, intima-media thickness [Sharma et al.2009]. Time-
dependent vascular histomorphic indices responded to increased SDG in combination with normal
and high SDG diets. The effects of SDG were better than flaxseed oil measured by histomorphic
parameters. [Sharma et al.2010]. Different histology sections with MMP-9 distribution visualized
the spatial localization of MMP in different segments of carotid/femoral artery endarterectomy
samples. The immuno-blank sections were used to do immunostaining of MMP-9. Different
histology sections with MMP-9 distribution visualized the spatial localization of MMP in
different segments of carotid artery endarterectomy as previously described [Brown et al.1995].
CYP11B2 gene expression of aldosterone synthase gene from excised artery samples was
amplified by polymerase chain reaction using Taq polymerase and specific nucleotides for
amplification at a preset temperature cycle of annealing and synthesis. The amplified product was
genotyped for segments of the CYP11B2 gene (DNA) using nucleotide sequencing similar to
methods described elsewhere for blood samples[Kupari et al.1998].
Secoisolariciresinol diglucoside is a lignan from flax seed. Studies in animals with chemical-
induced breast (mammary) cancer have found lignans (from whole flaxseed) and a pure lignan
(e.g. secoisolariciresinol product) to:

 Significantly slow the growth rate of tumors

 Significantly reduce tumor size
 Significantly reduce the number of tumors
 Increase the lifespan of animals with these tumors

In randomized, double-blind, placebo controlled clinical trials suggest that flaxseed

supplementation to premenopausal women can:
 Reduce recurring breast pain and tenderness associated with the menstrual period
 Decrease hormone concentrations (estrogens) during the menstrual cycle
 Reduce markers of breast cancer cell proliferation
 Mild, transient and clinically insignificant side effects.
 In ovary, Brevail (SDG)
Gastric digestion
SDG
Intestinal digestion
Enterodiol + Enterolactone
Outside ovaries, adrenal
glands generate estradiol
and estrogen. Brevail blocks
overproduction

Figure 6: Metabolism of lignin into enterodiol and enterolactone formation is shown for an
example of nutraceutical supplement Brevail®.

How SDG works in the body?: Digestion, Absorption, and Metabolism

The lignan secoisolariciresinol (SECO) is like a steroid compound with attached "hydroxyl"
groups. In flaxseed, SECO appears to exist as a complex attached to two glucose (sugar)
molecules-SDG. After SDG enters the intestines, it has its two glucose molecules removed to
form the "aglycone" SECO or 2, 3-bis (3-methoxy-4-hydroxybenzyl) butane-1, 4-diol. SECO is
converted by the intestinal microflora to trans-2, 3-bis [(3-hydroxylphenyl) methyl]-butyrolactone
or enterolactone (ENL) and 2,3-bis(3-hydroxybenzyl)butane-1,4-diol tetratms or enterodiol
(END)[Axelon et al.1982]. However, human studies are available on whole flax seed to provide
10 and 20 mg of SECO for the 5 and 10 gram daily doses, respectively[Hutchins et al.2000]. This
resulted in dramatic (4-16 times) and dose-dependent increases in the urinary concentrations of
ENL and END. Through portal system, ENL and END pass through liver to detoxify them by
sulfation and glucuronidation conjugation processes into water soluble saulfate and glucuronide
forms suitable for excretion in the urine. A much smaller fraction appears in the urine as cortisol
[McLean et al. 2001], and oxidative metabolites[Jacobs et al.1999].

Lignans: Breast Cancer Cell Growth

Breast cancer and cardiovascular protection by Brevail® containing SDG optimal doses was
reported in stringent, university based, human oral-dosing pharmacokinetics and steady state
studies in adult women[Setchell et al.2003]. In following description, preclinical trials on
Brevail® is summed up to understand the role of lignans in cancer protection, cardiovascular
protection during menopause. In previous study, a commercial SDG extract of flaxseed, 15
healthy postmenopausel women were randomized to doses of 25 mg, 50 mg, 100 mg and 200 mg
(5 women/dose) of an extract of Brevail® SDG as a single oral dose (200 mg to provide 50 mg
SECO). Blood and urine samples over the next 5 days showed high concentrations of SDG,
enterodiol and enterolactone by mass spectrometry. SDG in Brevail® is bioavailable and at 200
mg/day, provides 50 mg of SDG and maintains plasma enterolactone levels in the range of 63 +
12 nmol/L comparable to those of women at low risk for breast cancer. Earlier studies showed
that serum concentrations of enterolactone ranged 3-54 nmol/L were inversely correlated with risk
for breast cancer[Pietin et al.2001]. Those women with enterolactone levels of above 34 nmol/L
showed a marked reduction (0.38) in the odds adjusted risk for breast cancer. Flaxseed and its
primary lignan SDG exert a variety of complementary effects upon estrogen metabolism,
receptors, and signaling through their intestinal transformation products ENL and END. In an
experimental study, human-derived breast cancer cells (MCF-7) were kept in culture and
incubated with ENL or ENL plus estradiol. Investigators suggested that ENL prevents or reduces
the binding/metabolism of estradiol within these cells. However, still it is controversy but one fact
is established that ENL exerts a breast cancer protective effect[Setchell et al.1983]. In blood,
estrogens bind with a protein carrier called sex hormone binding globulin (SHBG) or sex steroid
binding protein (SBP). SHBG is produced in the liver and tightly binds with estrogens to act as a
delivery vehicle to tissues. Incubation of ENL with human liver cancer cells in culture stimulate
the synthesis of SHBG [Adlercreutz et al.1992]. Incubation of ENL with human SBP was shown
to efficiently displace estradiol from binding sites on the SBP protein to reduce estradiol effect on
tissue growth [Martin et al.1996].

Aromatase (an estrogen synthetase) is synthesized in peripheral tissues (adipose, muscle, and
liver), ovaries and healthy or cancerous breast [Reed et al.2001]. It regulates the conversion of
androgens into estrogens. Aromatase is inhibited in vitro by ENL or END (see Figure ) due to
antiestrogenic effects [Adlercreutz et al.1992]. These stuies support that phytoestrogens compete
effectively with endogenous mammalian estrogens, bind the ER, and prevent estrogen-stimulating
growth in mammals[Kurzer et al.1997]. In Asian continent, a preclinical study reported the effects
of lignan SDG in flax, and its mammalian counterpart ENL on the chemopreventive effects.
These studies show noteworthy reductions in both the size and number of tumors [Adlercreutz et
al.1997].

Whole flaxseed supplementation in meals to animals exposed to chemical carcinogens and a high
fat diet produced reductions in the size and number of breast tumors[Serraino et al.1992,
Thompson et al. 1996]. The fact revealed that flaxseed contains both fiber and the omega-3 fatty
acid alpha-linolenic acid (aLA) as the cancer-protective components that possibly reduce tumor
growth, progression, spreading (metastasis) and angiogenesis or new formation of new blood
vessels (capillaries) from pre-existing blood vessels[Neufeld et al.1999]. Angiogenesis is induced
by circulating vascular endothelial growth factor (VEGF). VEGF can "float" in the spaces
between cells, attaching to the interior lining of blood vessel cells, and then stimulate proliferation
and migration of new blood vessel cells [Ferrara et al.1997]. Same time, VEGF also stimulate
arteriosclerosis. Author implanted with a human-derived MCF-7 breast cancer cell line in
Sprague Dowling rats, showed angiogenesis and stimulated cell proliferation [Dabrosin et
al.2002, Sharma et al.2005]. In other study, potent metastatic activity (estrogen-independent
growth) after supplemented with flaxseed meal, showed significant reductions in tumor growth
rate, metastasis, VEGF, insulin growth factor-I (IGF-I) concentrations and receptor for epidermal
growth factor within large tumors[Rickard et al.2000, Kim et al. 1999].
Isolated pure SDG chemopreventive component in flaxseed was tested in two experimental
studies. One study with animals fed on a chemical carcinogen(group I), a high fat diet for 13
weeks then supplemented meal with flaxseed oil (rich in aLA and less SDG) (group II), and pure
SDG (group III)[Thompson et al.1996]. In all three groups, diets reduced tumor size but animals
supplemented with pure SDG showed maximum reduction in both tumor size and the average
number of new tumors formed[Thompson et al.1996a]. In a second study, pure SDG extracted
from flaxseed and fed to carcinogen-treated animals resulted in a 46% lower number of tumors
compared to those not receiving SDG, with no side effects[Thompson et al.1996b]. Studies
indicate that flaxseed contains very high amounts of secoisolariciresinol diglucoside (SDG)
inhibit the initiation and growth phases of mammary tumor development in rats, affecting both
tumor size and proliferative ability. The efficacy in vivo of SDG in breast cancer incidence among
postmenopausal women was expressed in relation to dietary and/or urinary lignan concentrations
in East Finland [Haggans et al.2000]

Flaxseed Supplementation: Estrogen Metabolism

SDG can alter the estrogen metabolism and action of estrogens [Brooks et al.2002]. In this regard,
three classic studies put evidence of 2OH-estrogen benefits and estrogen action-modifying effects
of flaxseed lignan, SDG in lase decade. A description is given here for better insights. In first
study, twenty-eight women nuns on 7-week diet supplementation on 1: their usual control diet, 2:
5 gram/ day supplement of flaxseed meal, and 3: 10 gram/day supplement of flaxseed meal
[Haggans et al. 2000]. After a "washout" period of 7 weeks followed each 7-week dietary
treatment period showed a high concentration of 2-hydroxy estrogen (2OH-E; the "safe" estrogen)
in the urine of the subjects with 10 g/day dose than other subjects. Additionally, the ratio of 2/16-
OH estrone (a protective hormone) increased with flaxseed in 10 g/day dose than the 5 g/day dose
and the control diet. In second follow-up study, effects of flaxseed and wheat bran fiber
supplementation on estrogen metabolism were compared in 16 healthy premenopausal women
over a period of 8 menstrual cycles[Brooks et al. 2002]. The women were asked to consume their
diet and specially prepared baked goods (cookies and muffins with low fiber and bran)
containing: 1: 10 g ground flaxseed (group I), 2: 28 g wheat bran fiber(group II), 3: 10 g ground
flaxseed + 28 g wheat bran fiber(group III), or 4: no added lignan or fiber source (group IV) for
two consecutive cycles. Only two treatments of flaxseed supplementation produced significant
alterations in urinary markers of estrogen metabolism and significantly increased 2OH-E and
2/16- OH estrone ratio. Study suggested that SDG is the primary estrogen metabolism modifier
present in flaxseed. Flaxseed and its products enterolactone and enterodiol decrease cell
proliferation in vitro, and might influence factors that affect the hormone concentrations in
humans is likely a increased protection against hormone-dependent cancers [Hutchins et al.
2000]. In third study, 116 women who had experienced severe cyclical mastalgia for a preceding
6 month interval were supplemented with flaxseed (25 g/muffin) or placebo muffins over 3
menstrual cycles. After three cycles the reduction in breast pain, swelling, and lumpiness was
significantly lower in the women eating the flaxseed muffin. These women also showed an
increase in urinary mammalian lignans (ENL and END) and a change in blood estrogens (see
Figure 6).

Another type of phytoestrogen of clinical significance is isoflavones, abundant in soy foods.

To compare the effects of flaxseed and soy upon estrogen metabolism, postmenopausal women
received a placebo muffin (control) or muffin with 25 g ground flaxseed or soy daily for 16
weeks[Lewis et al.2006]. At the end of supplementation, only the group receiving the flaxseed
muffin showed significant increases in 2OH-E and the 2/16 OH estrone ratio. During menopause,
breast tenderness and pain caused cyclical mastalgia accompanied by breast swelling with
elevated risk of breast cancer. Study indicated that flaxseed is effective in relieving symptoms of
cyclical mastalgia without significant side effects and might be considered as an alternative
treatment for cyclical mastalgia. Its putative mechanism of action may be via the anti-estrogenic
effects of the lignans [Goos et al.2000]. Other facts in the postmenopausal women receiving the
flaxseed muffin cellular factors indicated the low tumor growth by 21-33%, accompanied with
significant increases in urinary lignans (ENL and END) with no adverse effect, while neither were
altered in the placebo group[Clark et al. 1993].

Safety and Tolerability of SDG

The safety and tolerability of SDG in all of these preclinical and animal studies showed no
significant adverse effects or altered biochemical safety parameters. Basic ground flaxseed (5-50
g/day) consumption is equivalent to 10-350 mg of secoisolariciresinol, the absorbable lignan
"SECO" component in SDG[Nesbitt et al. 1999]. Both ENL and END, derived from dietary SDG,
have revealed no mutagenic effects on mammalian cells in culture[Kulling et al. 1998].

Still major questions remain unsolved on the success of SDG benefits in menopause as following,
if:

 Flax seed protein SDG in low, medium and high doses how breaks down in cells and
causes lipid lowering but higher triglycerides in serum
 Any active role of SDH hydroxylase enzyme in digestion or absorption
 Flax seed protein SDG mixed in flax seed oil modulate lipid factors LDL, HDL, platelets
and enzymes are responsible of reduction in blood lipids, atherogenic events
 Cardiovascular artery structures and heart are the main targets of SDG to combat
hypercholesterolemia and atherosclerosis to reduce risk of CVD
  Vitamin E as diet supplement mixed with SDG enhances the cardioprotective action as
antithrombotic and antioxidant to restore carotid, renal and femoral arteries and controls
the dyslipidemia
 Dyslipidemia and atherosclerosis are simultaneous biological processes and serve as
visible risk of hypercholesterolemia by measuring blood lipids, antioxidant tests and
vascular structures by cationic contrast agents
 Any side effect(s) such as diarrhea (Brush border membrane ATPase), asthenia, fatigue,
cramp, dose – BP changes, hypotension(Angiotensin II), antioxidant effect(SOD),
immunostimulatory effect(cytokines) after treatment of high doses of SDG or flax seed oil

II. Mechanism of soy isoflavones in menopause

Soybeans contain 35–40% protein on a dry-weight basis contains 90% of 2 storage globulins, 11S
glycinin and 7S b-conglycinin. Glycinin has A (acidic) and B (basic) subunits, whereas b-
conglycinin has a, a#, and b subunits [Torres et al. 2006]. Isoflavones (ISF) are major soy
phytoestrogens present in soy foods and require washing in alcohol for removal [Anthony et al.
1996]. Soy foods and soy-based infant formulas are rich sources of ISF and contain;1–4.2 mg
ISF/g, whereas soy ISF supplements contain up to 500 mg ISF/g. Genistin, daidzin, and glycitein
are the main soy ISF. Both genistin and daidzin are conjugated to sugars as Glycosides.
Glycoside ISF cannot be absorbed unless hydrolyzed and converted to the bioactive forms,
genistein and daidzein, both aglycones, by intestinal microflora or in vitro fermentation. Aglycone
ISF that are more bioavailable and active than the glycoside ISF. ISF can bind to both a and b
isoforms of estrogen receptor (ER). However, their binding affinity to ERb is ;20 times higher
than that to ERa, and their efficacies of activating the binding of ERb to estrogen response
elements (ERE) of target genes are 500–850 times higher than that of activating the binding of
ERα to ERβ [Kostelac et al. 2005]. This feature may contribute to their opposite effects on
regulating gene expression and physiological functions such as suppression of cell proliferation.
Selective receptor binding may confer on ISF the ability to regulate physiological functions in a
different way from estrogen.

The hyolipidemic effect of soy protein and ISF was reported by Ricketts et al. 2005, as first
meta analysis of mean intakes of 47 g/d (range 17 to 124 g) of isolated or textured soy protein
resulted in significant reduction in total cholesterol by 9.3%, LDL-cholesterol by 12.9%, and
triglycerides by 10.5%, with an insignificant change in HDL cholesterol levels, compared with
animal protein. However, FDA approved claim of soy proteins as cholesterol lowering with no
mechanistic evidence. A recent study in postmenopausal women showed that daily
supplementation of 25 g of soy protein and 101 mg of aglycone ISF lowered LDL cholesterol and
apolipoprotein B levels by 11% and 8%, respectively, and reduced systolic and diastolic blood
pressure by 9.9% and 6.8%, respectively, in hypertensive women [Welry et la. 2007].
 Meta-analyses of randomized controlled trials suggest that soy ISF intervention significantly
attenuates bone loss of the spine [Ma et al. 2007] and markedly decreases urinary
deoxypyridinoline, a bone resorption marker, and increases serum bone-specific alkaline
phosphatase, a bone formation marker, in menopausal women [Ma et al. 2008]. No significant
effects of ISF on bone mass density or biomarkers of bone metabolism have been reported in a
study in which soy protein was supplemented and ISF-poor soy protein was used as control
[Cheong et al. 2007]. These data indicate that soy protein may interfere with the effects of ISF
either by masking or antagonizing its effect.

For the value of soy protein in reducing menopause symptoms, a meta-analysis of 25 trials
published between 1966 and 2004 indicates that soy phytoestrogens did not improve hot flashes
or other menopausal symptoms [Krebs et al. 2004]. Intake of soy supplements for treatment of
menopausal symptoms in patients with early breast cancer did not show any significant effect on
menopausal symptom scores or quality of life after 12 wk compared with placebo [Mac Gregor et
al. 2005]. Therefore, there is no consistent evidence to support any beneficial effect of soy intake
on menopausal symptoms at this stage.

Many animal and human studies have been conducted to determine the association between
soy intake and breast and prostate cancers. Human cancer cell lines have been used in in vitro
studies to understand the cellular and molecular events involved in the regulation of cell
proliferation and apoptosis by soy components. However, the existing results from clinical trials
are inconclusive as evidenced in following reports. A recently published Japanese collaborative
cohort study suggested that consumption of soy foods such as tofu, boiled beans, and miso soup
has no protective effects against breast cancer [Nishio et al. 2007]. Moreover, soy ISF may
stimulate epithelial cell proliferation in the breasts of premenopausal women in clinical studies.
Dietary ISF significantly decreased the risk of prostate cancer in Japanese men [Nagata et al.
2007].

Excessive soy intake has been known since 60s to be responsible for the development of
goiter, including thyroid enlargement, in infants fed soy-flour–based formula without iodine
fortification. It was confirmed now in other studies as ISF markedly suppressed the binding ability
of hepatic thyroid hormone receptor to the thyroid hormone response element of the target genes
[Son et al. 2001, Huang et al. 2005].

These findings suggest that intake of soy may reduce the efficiency of thyroid hormone
function and that soybeans may contain goitrogens that can interfere with the utilization of iodine
or functioning of the thyroid gland and cause thyroid problems. In US and Canada, 25% infants
represent a group exposed to a large amount of soy ISF. Blood ISF concentrations in those infants
are 13,000–22,000 times higher than plasma estradiol levels in early life and are 6- to 11 fold
higher on a body-weight basis than the dose that has hormonal effects in adults consuming soy
foods [Setchell et al. 1997]. However, the impact of excessive intake of ISF on early development
and on endocrine and reproductive functions in humans remains unclear.
 Soy and isoflavones have been used safely in humans previously to investigate their effects on
blood lipids and blood pressure [Anthony et al.1996]. Another fact was reported as reduced
calcification deposits in carotid and femoral arteries using Micro-CT. The effectiveness of soy
isoflavones on reducing calcification in vascular tissues was evaluated before surgery by ex vivo
micro-CT procedure [Mohr et al. 2005]. In a 3 x 2 factorial experiment, with soy having 3 levels
1.2, 2.4, 4 g/Kg body weight (7.5%, 15%, and 22.5%) with vitamin E having 3 levels (20 mL, 30
mL, 40 mL) plus two additional groups: sham and hyper-cholesterolemic groups, diet was
efficacious in preventing atherogenesis in a golden hamster model of atherosclerosis [Lucas et
al.2006]. However, low dose of vitamin E met the recommended level for growth and
maintenance of golden Syrian hamsters [Lucas et al. 2004]. The high dose of vitamin E was based
on the findings that soy isoflavones in combination with vitamin E in diet produced a synergistic
effect on cardiovascular protection in animals. In other study, incorporation of soy protein with
normal isoflavone content showed greater effect on the IGF-1 mRNA than the isoflavone depleted
soy protein based diet [Krebs et al. 2004]. It indicated that isoflavones may have a role in
enhancing the synthesis of IGF-1 at vascular level. Furthermore, in human carotid arteries
[Marini et al. 2007, Krebs et al. 2004] soy protein supplementation increased serum IGF-1 levels
[McLaughlin et al. 2011]. Circulating lipoproteins concentrations were reported to correlate
positively with thrombus mass in elderly female subjects with antihypertensive enhancing
properties of isoflavones as clinically relevant [Lazennec et al. 2001]. Observations indicate the
need of exploring a lipoprotein pathway with mechanism(s) by which soy isoflavones might
enhance the lipid lowering.

Several studies have demonstrated the effectiveness of soy proteins and/or isoflavone
ingredients in atherosclerosis [Xiao et al.2008]. Soy seed is rich source of alpha linoleic acid
(ALA). ALA rich soy improves platelet function and offers protection against CVD. Other
modulatory components in soy are isoflavones. For instance, soy isoflavones has been shown to
increase HDL by 10% in subjects with high lipids when compared with untreated controls
[Lephart et al. 2004, Gallagher et al. 2004]. Soy supplementation has shown a HDL increase by
lipid modulation with improved dyslipidemia in elderly subjects [Shu et al. 2001]. Conceptually,
synthetic isoflavones modulate 7α Hydroxylase and acyl-CoA cholesterol transferase with result
of low serum total and LDL-cholesterol while increasing HDL-cholesterol concentrations.
However, ground soy beans also causes increased plasma TG concentrations[FDA 1999]. In
older subjects (between ages of 65-79 years) with X-Ray evidence of at least minimal
atherosclerosis and animal studies from our institution demonstrated that both soy [Ascencio et al.
2001] and isoflavones [Xiao et al. 2007, Shu et al. 2001] can positively affect lipids in such a way
that LDL and cholesterol are reduced and dyslipidemia is improved.

Similar to soy and isoflavones, data on the efficacy of soy for prevention of elderly
atherosclerosis are inconsistent. Our prospective, randomized, double blind, placebo-controlled
multicenter study indicated bioactive foods not necessarily prevent dyslipidemia or biomarkers of
lipid metabolism [Sharma 2010, Nishio et al. 2007]. We have no explanation on increased TG
levels after flaxseed feeding. However, soy appears to be effective in the context of soy protein
and can increase cholesterol desaturation and coronary wall thinning in women with lower doses
of 70-90 mg/day [Anthony et al. 1998, Lephart et al. 2004]. However, previous study indicated
that soy protein normalized HDL possibly related with ovarian hormone deficiency [Anthony et
al. 1998, Lephart et al. 2004] but mechanism for limited or no effect on atherosclerosis plaques
and wall thickening related to the use of soy high dose is less known while results were
impressive showing reduced lesions in 73% cholesterol fed rabbits[Miniello et al. 2003]. Soy
protein dose-response human study is not available to conclude lowest effective isoflavone level
in diet to reduce cholesterol [Xiao et al. 2008]. Previous studies in hypercholesterolemic rabbits
suggested preventive effect of dietary soy on atherosclerosis lesion formation. [Welrey et al.
2007, SANA 2008, Sacks et al. 2006].

down-regulation of gene expression for receptor activator of NFkappa-B ligand (RANKL) and
osteoprotegerin (OPG) gene induced by soy protein was reported by previous studies to show that
soy isoflavones trigger the regulatory steps in protein transcription by modulating mRNA at gene
level and synthesis of regulatory proteins in bone formation.[Franklin et al.2006]. In other study,
increased mRNA levels of alkaline phosphatase (ALP), collagen type I (COL), and osteocalcin
(OC) were shown associated with enhanced bone formation [Soung et al. 2006]. Microarray
analysis was performed on liver using Affymetrix GeneChip Rat 230 2.0 to study interaction
between E2 and SPI for modulated expression profile of 225 genes involved in fatty acid
biosynthesis or glucocorticoid signaling and those involved in cholesterol metabolism. The
different hepatic gene expression signatures evidenced the role of soy protein different from 17β
estradiol treatment.[Singhal R et al. 2009]. Recently, several studies highlighted the role of soy
protein induced gene expression of TGF-β1[Chen et al. 2012], Fc γ R-mediated phagocytosis
[Wang et al. 2011], MDM2 oncoprotein with MDM2 SNP309 and TP53 R72P polymorphisms
[Koh et al. 2011], GSTM1, GSTT1 and GSTP1 polymorphisms [Steck et al. 2007], glutathione S-
transferase P1 (GSTP1), Ras association domain family 1(RASSF1A), ephrin B2(EPH2),breast
cancer (BRCA1) promotor genes[Vardi et al.2010], and miRNAs differentially expressed in
prostate cancer cell lines [Rabiau et al. 2011].

Major points can be summarized on consumption of soy protein and beneficial effects as
following:

 lower blood LDL cholesterol in hyperlipidemic subjects

 beneficial effects of soy ISF in the prevention of bone loss in postmenopausal women.
 inconclusive positive impact of soy protein or ISF on biomarkers of prostate cancer
 no evidence of soy protein and ISF in relieving menopause symptoms and prevention of
breast cancer
 antithyroid actions of soy in both animals and humans
 hypolipidemic effects of soy consumption with no information on amino acid composition
of soy protein subunits or composite peptides
  reduced blood cholesterol levels or decreased risk for heart disease with no evidence or
 inadequate mechanism.
 identification of the bioactive components in soy and investigation of the molecular
mechanisms

III. Mechanism of Vitamin E in menopause

Cai et al. 2008 supported the synergistic effects of soy seeds and isoflavones dependent on
vitamin E level in diet with increase in benefits of isoflavone and vitamin E in diet. Authors
showed a reversal of bone loss by administering soy in diet. In other study, Chai et al. 2011
suggested the role of vitamin E in reducing aortic fatty lesions. Major focus of research was to
explore the role of vitamin E in bone quality [Arjamandi et al.2002], reversing the bone loss and
reducing thrombosis in experimental animals models [Lucas et al. 2006, Smith et al.2005].
Vitamin E acts to improve bone quality and increases in bone dry weight, protein, and mRNA
transcripts for osteocalcin, type I alpha-collagen, and IGF-I. These data demonstrate that high-
dose vitamin E has pronounced effects on bone quality as well as matrix protein in old mice by
augmenting bone matrix protein without reducing bone mineralization as evidenced by unaltered
bone density [Arjmandi et al. 2002]. Vitamin E has chromanol ring and exhibits antioxidant
action.
Superoxide anion O2-

H2O2

*OH
Scavenger action: TH + ascorbate  TH- + ascorbate*
-

Figure 7 : A scheme of vitamin E is shown in oxidative action to remove superoxide anion.

Tocopherol in diet supplements have been shown to influence susceptibility of LDL to oxidation
[Lucas et al. 2006] but no confirmation on decreasing disease risk or outcome [Blumberg et al.
2002]

Evidence Available on Beneficial Effects of Nutrients in Menopause

In last decade, nutraceutical research in menopause prevention was exciting especially in clinical
trials and inventions [US patents 0297230, 0248693, 0274746, 0181110, 0182943, 0077193,
0234948, 7763292, 0206721, 0141178, 0226989, 0160616, 0221469]. For interested readers,
major breakthroughs are cited as below in formulations of menopause prevention.
In recent years, several nutrition formulas are proposed in menopause women in keeping in
consideration of following benefits.

Vitamin C is a water-soluble antioxidant. RDA is

 protects proteins from oxidation
 repairs collagen and acts in stomach relaxing as antistress
 hypertoxicity causes diarrhea

Vitamin D is
 regulates calcium absorption
 synthesized in skin
 abundant in fish, liver, butter, egg yolk and recommended in osteoporosis
 stimulated by estrogens to make more vitamin D3 hormone
 boron and magnesium enhance vitamin D utilization

Vitamin A is fat-soluble and its water soluble precursor, beta-carotene maintains integrity in
intestinal walls in absorption of minerals
 beta carotene conversion to vitamin A needs zinc containg enzyme
 abundant in yellow and deep green sprouts, green vegetables or fruits, carrots, sunflower
lettuce

Vitamin E recommended dose is 400-1200 IU per day to stop hot flashes.

 enhances estrogen utilization from adrenal glands or fat tissues
 stimulates prostaglandin production
 alleviates breast tenderness, reduces skin wrinkles, and protects the bone marrow from
toxicity
 stabilizes blood vessels by reducing vascular dilatation in response to hormone change
 abundant in sprouted wheatberries, salads, wheat germ oil plus fiber

Vitamin B6
 prevents osteoporosis, arteriosclerosis and relieves from heart disease, depression and
fluid retention
 stimulates progesterone

Silicon is second most abundant mineral.

 improves calcium metabolism
 vegetable silicon controls the osteoporosis
 main sources are oats, barley, brown rice, coconut, muskmelon, centelope, apples,
cherries, apricots, blackberries, equisetum (horse tail tea)
Boron recommended dose is 3 mg per day to increase blood estrogen levels by two fold.
 produces active form of vitamin D and estrogen
 reduces urinary excretion of calcium (calcium retention) and magnesium
 high boron intake increases magnesium, calcium in bones and overall bone metabolism
 abundant in alfalfa and kelp, spinach, snap beans, cabbage, lettuce, apples, leafy greens,
grapes, legumes, muskmelon leaves, nuts, grains.

Magnesium
 converts to active vitamin D3 and fixes high calcium and low potassium in body
 improves calcium absorption
 abundant in morning eggs, liver, leafy greens, whole grain, legumes, seeds, almonds,
black-eye peas, curry, mustard powder, sprouted lentils

Potassium
 performs sodium-potassium pump activity, heart beating, nervous conduction
 rich in dulse, kelp, soybeans, seaweeds, banana

Chromium
 improves glucose tolerance and insulin resistance to cause low circulating insulin in
menopausal women
 stops weight gain, stress, irritation, tiredness, and improves blood cholesterol and sugar
levels

Zinc
 is part of metalloprotease enzymes
 stimulates transformation of vitamin A
 rich in oysters

Tryptophan is amino acid.

 relieves from depression, irritability, insomnia, carbohydrate craving

Gamma linolenic acid is essential fatty acid and stimulates prostaglandin synthesis.
 abundant in oils of black currant seeds, borage, primrose supplements and vegetables.

Proanthocyanides

DHEA breaks down to estrogen and androgens. It is recommended 100 mg per day or above.

ANIMAL STUDIES
Animal studies are available on clear benefits of soy isoflavones in hypolipidemic and cholesterol
lowering [Mezei et al.2003, Yang et al. 2002, Yang et al. 2007], bone quality [Arjmandi, 2002],
reducing blood pressure [Lucas et al.2006], diabetes and obesity [Liu et al. 2010]; flax seed
lignans in reducing atherogenesis [Lucas et al. 2004]; vitamin E in cancer and antioxidant activity
[Lucas et al. 2006, Smith et al.2005]; blue berry in lipid lowering [Devareddy et al. 2008].
Limited studies report the mechanism of phytoestrogen action in menopause using ovariectomy as
animal models of menopause including rabbits [Prasad et al.1997,1999], rats [Arjmandi et
al.2002,Prasad 2000a,2000b,Devareddy et al. 2008, Khalil et al.2005, Johnson et al.2008,
Franklin et al.2006], mice [De Angel et al. 2010, Li et al.1999] and golden hamsters [Lucas et al.
2004, 2011].

RECOMMENDATIONS ON FOOD SUPPLEMENTS IN MENOPAUSE

Fibrocystic breast disease, menopause, osteoporosis, premenstrual syndrome (backache,

irritability, anxiety, irritability), uterine fibroids are associated risks with Western life style with
high fatty food, smoking-alcoholic habits. I propose a three-step approach of nutrition in
menopause. First step is food and menopause meal planning and keeping natural progesterone1
normal (take Bi-est or Tri-est) in early years of menopause symptoms. Second is reducing oral
progesterone or ERT to minimal or not at all to replace it with unrestricted safe use of
nutraceuticals and herbal formula for clear benefits along with menopause meal®. Third step is
exclusive herbal formula-R® with iodine for thyroid management and no oral estrogens or
surgery.

First step: For women, I recommend nutritional therapy by fruits and supplements to maintain
metabolism and reducing fat energy intake (-10 to -15%) by specific phytonutrient make up and
alkalinizing effect.
 foods as a blend of watermelon, bananas, raisins, pears, citrus fruits, plums, peaches,
papaya, mangoes, dates as unrestricted fruits intake (to reduce abdominal bloating,
backache, irritability and anxiety).
 vegetables as blend of beets, beet greens, eggplant
 garlic, soy, acidophilus, flaxseed oil, beet crystals, kamut grass, bee pollen taken daily
with safety instructions as per need arises with no restriction.
 almond nuts
 Four herbal-mix (onion, ginger, garlic, turmeric), with sesame oil in salads

1
Women without menopause symptoms of hot flash have a negative lifestyle response to ERT with Premarin
Second Step: If fibrocysts developed in breast, reduce oral progesterone or estrogens by Premarin
ERT2 and follow recommended following diet plan (see Menopause Nivaran(@) with following
supplements:

Diet plan:

 advice is to eat low fat, no caffeine, no alcohol in diet

 Unrestricted safe consumption of fruits and green vegetables to get bioflavonoids
 nuts and unrestricted wheat germ intake to get Vitamin E
 unrestricted eating soy and pear products
 use Four herbal-mix- onion, garlic, turmeric and ginger with black currant oil 1gm a day
or flaxseed oil 1 gm a day to help inflammation

Supplements and nutrients intake plan:

 Essential fatty acids: 1000 mg a day to balance hormone

 Vitamin C: 1000 – 2500 mg a day to boost immune system
 Evening primrose oil: 1500 – 3000 mg a day to reduce the size of lumps
 Coenzyme Q10: 100 mg a day to provide intracellular energy to detoxify and immunity
boost, stimulant of adrenal glands
 Herbs mixture: aloe vera 2 ounces twice a day, turmeric 100-200 mg a day, ginger 500
mg twice a day, black cohosh 40 mg twice a day, quercetin 2 mg a day, licorice extract 10
drops, dong quai 15 mg a day all to reduce hot flash and as anti-inflammatory blend

Menopause Nivaran(@) diet plan

Half pint blackberries

1 ripe banana
1 spoon brewer yeast
1 cup soy milk

Mix them and

Consume for 7-15 days a restricted food including only steamed white turnip with greens mixed
with black pepper and half spoon almond oil with 8 glasses water

2
Continuous ERT shows side effects of breast tenderness, abdominal bleeding without change in heart disease
Third step: If estrogen and progesterone levels fall below with clear symptoms of advanced
menopause and breast tenderness or cyst formation with detected uterine fibroid formation or
ovarian cancer, I recommend the unrestricted Herbal-Formula R(@) intake as long it gives relief
with following plan:

 Take broccoli to supplement vitamin K

 Take vegetable protein and no animal meat
 Take blend of Calcium 2500 mg + Magnesium 1000 mg + Boron 3.5 mg mixture in a day
 Unrestricted pear and soy products

Herbs plan:

 Herbs mixture: turmeric 100-200 mg a day, ginger 500 mg twice a day, black cohosh 60
mg a day, quercetin 2 mg a day, licorice extract 10 drops, dong quai 5 mg a day all to
reduce hot flash and as anti-inflammatory blend to help bone formation and inflammation
 Green mixture: 1 spoon of dulse, kelp, pudina, tulsi mixture or Japanese sea vegetables
 Vitamin C 3 gm a day as antioxidant to boost immune system
 Alpha lipoic acid 100 mg a day to balance effect on uterus lining
 CoQ 10 un 100 mg a day dose to boost immune system

I describe them in next section on herbal and nutraceutical based pharmaceutical formula.

Some of the knowledge based beneficial food sources are recommended as following in relieving
premenopause symptoms in early stages.

Dietary Sources: Other protective foods are alfalfa, anise, barley, carrots, cherries, clover, fennel,
garlic, green beans, hops, licorice, oats, peas, pomegranates potatoes, rice, rye, sesame, sage
seeds, wheat and yeast.

Garlic has allicin chemical as natural antibiotic, and lowers down lipids in blood.

Soy products reduce menopausal symptoms. One cup of soybeans is recommended to get 300 mg
isoflavones.

Acidophilus is bacteria. It co-habits with lactobacillus in intestine.

 performs functions of immunity, metabolism, enriching microflora
Whole flax (Linum usitatissimum L.) ground meal, powder or intact seed contains 28% dietary
fiber, (7 – 10% soluble fiber, 11 - 18% insoluble fiber), 40% fat (73% of it being polyunsaturated
fatty acids), and 21% protein. Other flax seed nutrients include vitamin E and B, sterols, and
mineral nutrients such as calcium, iron, and potassium. More than 50% of the fat in flax seed is an
essential fatty acid called omega-3 fatty acid (alpha-linolenic acid, ALA ), which makes flax seed
the richest plant source of omega-3 fatty acid. Flax seed is rich in antioxidants, such as (also
lignans or phytoestrogens) and other phenolic molecules.
 flax seed oil contains no dietary fiber.
 High in magnesium, lecithin, and omega 3 fatty acid alphalinolenic acid (ALA)
 Produces lignans as protective breast cancer
 Improves progesterone and estradiol ratio [Phipps,1993]
 Flax promotes colon health
 promotes cardiovascular health in heart disease, triglyceride and Cholesterol Lowering
 provides fats that are precursors for brain building
 promotes healthy skin and burns fat to make slim
 lessen the severity of diabetes by stabilizing blood-sugar levels
 works best in the body when it's taken along with antioxidants, such as vitamins E,
carotene, and other nutrients, such as vitamin B6 and magnesium.

Red Beet crystals are good for blood

 Rich in vitamins, minerals

Kamut grasses concentrate or sprouts are prepared from kemut grains with butter flavor.
 High in protein, beta carotene, chlorophyll

Bee pollen
 Golden dust is full with natural enzymes

NUTRACEUTICALS TAKEN IN RECOMMENDED DOSE:

American Nutraceutical Association (ANA) has established recommended dose schedule of

different nutraceuticals in general. For more specific details, readers can read the websites and
monograms [ANA monogram]. In following section, I cite some of established remedies of
nutrition and diet supplements in menopause.
 Ginseng (Panax quinquefolius) shows phytoestrogenic activity in menopause
 Don Quai (herb angelica) improves progesterone metabolism. In menopause, it is
recommended with vitamin E and folic acid
 Dang gui (angelica sinensis) constricts the relaxed uterus and soften a cramping uterus;
reduces atherosclerosis, pain syndrome, spasmodic symptoms
 Vitex or chest berries reduce pain, menopausal distress by stimulating pituitary to produce
progesterone and regular periods
  Black cohosh (Cimicifuga racemosa) shows estrogenic activity, pain reliever, reducing hot
flashes, vasodilatory effect, anti-inflammation, lowering blood pressure, muscle relaxant
 Red clover (Trifolium pretense) herb is high in isoflavones often recommended in
menopause as Promensil® containing 40 mg isoflavones daily.
 Siberian ginseng (Eleutherococcus senticosus) increases energy, environmental stress
reliever, reducing fatigue, colds, flus, emotional sensitivity
 Catnip, Chemomile, Passion flower, Lemon balm, Hops, Valerian root, Skullcap reduce
nervous tension and insomnia
 Cooked Rehmannia (Rehmanniae glutinosae), Cornus (Cornus officinalis), Peony
(Paeonine lactiflorae) show replenished blood and essence, relieving from weakness, pain,
spasm, cramps, irritability, mood swings, fatigue, dryness, irregular periods, irregular
bleeding, strengthens bones, sweating, and enhances libido.
 Graphites remedy shows relief in night aggravation
 Sepia remedy shows relief in mood swings, pelvic, uterine weakness
 Sabina remedy shows protection against fibroids, abnormal menstruation
 Sanguinaria remedy shows relief in hot flashes
 Sarsaparilla remedy shows relief against urinary incontinence

KNOWN FACTS ON NUTRITION IN MENOPAUSE TO REDUCE HOT FLASHES

 Flax seed enhances progesterone/estradiol ratio

 Multivitamin and mineral supplements as mixture of A, B2, B5, B6, B9, E with Cr, Cu,
Mg, Se, Si, Zn give comfort in the hot flashes and protect bone marrow from cancer
 Vitamin C builds connective tissues (bones and cartilage); makes strong bones at low risk
of fracture; protects from cancer; protects bone cells from toxins; increases bone density
 Vitamin D intake stimulates vitamin D3 formation and calcium absorption in kidneys
 Boron, Magnesium and calcium interplay in bone formation and stop arthritis
 Silicon is good supplement in slowing down connective tissue loss, osteoporosis and
Arthritis
Active life style and physical activity

The author proposes the concepts of biochemical changes in experimental isolated breast cells
based on available experimental isolated cells in a step-by step manner leading to arrested growth
or breast cancer cell killing as explanation of benefits of reduced breast cancer risk while
relieving women from menopause.

 The effect of herbs is measured by tumor volume, animal weight, tumor size shrinkage,
inhibited cell growth, % loss of cell viability, inhibited biomarkers (enzymes),
 What herbs do on host cells undergoing benign? The aerobic glucose oxidation in normal
ovary, breast and adipose cells leads to enhanced mitochondrial oxidative phosphorylation in
presence of oxygen. High concentration of CO2 suffocates the benign cells and anerobic glucose
oxidation result with halt in mitochondrial energy. So, it does not favor the host normal cells to
undergo benign cellular damage.
 In advanced menopause breast and ovary cells at risk demonstrate high glucose consumption,
high glycolytic rate, rapid cell proliferation, lactic acid accumulation, extracellular acidic low pH,
low glucose available, oxygen deprivation or hypoxia further aggravated by deficiency of
estradiol and estrogen replacement therapy. Overall, it resists the estradiol and progesterone
production and natural progesterone therapeutic action. In following description, I describe
concepts on transformation of progesterone overtreated breast tumor or ovarian cells to undergo
process of benign and beyond to malignancy (see Figure 8).

Concept 1: Breast tumor cells starve by blocking anerobic glucose utility by herbal active
component(s): The glucose utility block augments the aerobic energy metabolism in host. The
block leads the lactate dehydrogenase inhibition and cytosolic TCA cycle (2,3 dimethoxy-5-
methyl-1,4-benzoquinone (DMBQ) in coenzyme Q10. The blocked glycolysis also favors
mitochondrial oxidative function through complex I-IV (example riboflavin, FAD, FMN
derivatives)

FF
In Cancer Elevated Glycolysis (Anaerobic glucose) is normalized by Mitochondrial Oxidation

Low Oxygen/CO2 ratio Anerobic glucose utilization and lactate accumulates

Low NADH/NAD ratio Causes glucose depletion and high energy demand.
Low ATP/ADP ratio Herbal formula inhibits LDH inhibition and blocks
electron transfer and ATP supply to cancer cells

GlucoseF1,6PLactatePyruvateAcetyl CoA Lactate dehydrogenase inhibition by

herbceuticals
OxaloacetateCitrateAconitateKetoglutarateSuccinateFumerateMalate

Flavones, Xanthones reduce the rate NADPH/NADH; FADH/FAD

of mitochondrial oxidative
phosphorylation
UbQCyt a3Cyt ICyt IVCyt bCyt CO2

In mitochondria, electron transfer and Oxidative phosphorylation blocked

Hypothalamus GNRHPitutary …OVARY  Testosteone, Progesterone, Estrogen

Figure 8: How herbs and nutraceuticals act? A diagrammatic sketch of blocked anaerobic glucose utility sites in
glucose oxidation and TCA cycle. The metabolic steps are shown for enzymes: fructose 1,6-bisphosphatase(A),
acetate-CoA ligase, malate synthase, isocitrate lyase, aconitase, phosphoenol carboxylase,/carboxykinase, glycolate
oxidase, phosphoglycolate phosphatase, glycolaldehyde dehydrogenase, pyruvate carboxylase, citrate lyase,
ferridoxin oxidoreductase, 2,3-diphosphoglycerate mutase, propionyl CoA carboxylase, malic enzyme and acetyl
CoA carboxylase. The mitochondrial respiration shows metabolic steps of oxidative phosphorylation and electron
transport chain.
Concept 2: Oxygen depletion and hypoxia in menopause induced tumor: High oxygen is not good
for tumor cells. High oxygen in tumor cells causes high mitochondrial respiration (where oxygen
is a substrate for mitochondrial complex IV) and high alkalinity.

Concept 3: Inhibition of lactate dehydrogenase (LDH-V M4): The LDH plays active role in
development of benign or malignancy as enzyme LDH generates product NAD+ and 2 pyruvate
molecules from one glucose. Immediately NAD+ is consumed as cofactor of glyceraldehydes-3-
phosphate dehydrogenase to push ATP more production through anaerobic metabolism catalyzed
by phosphoglycerate/pyruvate kinase. While pyruvate molecule gets into acetylCoA by pyruvate
dehydrogenase in aerobic metabolism.

Guidelines and Recommendations on Nutrition Supplementation in

Menopause
In the light of present knowledge on benefits of bioactive foods, nutraceutical and herbal
supplements I recommend following guidelines with recommendations as shown in Figure 9.

Menopause symptoms, no cancer, Natural Progesterone ¼ TSP on skin

Stage 1: No Food intervention

Nervousness, hot flash, insomnia, irritability
Black cohosh, dong quai, lignans/isoflavones
Herbal Balance-R®  Biest 2.5 mg +
Natural progesterone + 1000 mg vitamin D
Calcium citrate 1.5 gm + Magnesium 5 mg
Boron 3 mg per day

Stage 2: Herb and food supplements added

Fibrocystic breast disease or fibroids Iodine 750 mcg -12.5 mg a day

Herbal Balance-R®  Pro-Apoptosis Mix®

Figure 9: Step by step approach is suggested to prevent early menopause symptoms with risk of
cancer.
ALTERNATIVE APPROACHES OF NUTRACEUTICALS IN MENOPAUSE
Other study suggested the benefits of dietary flavonoids [Hardcastle et al. 2011], green tea Tai
Chai [Shen et al.2011], blue berry [Devareddy et al. 2008], dietary catechins [Arts et al.2002],
phytoestrogen-rich diets [Cassidy et al. 2003, Garrido et al.2003, Gikas et al. 2005, Usui et al.
2006], cruciferous vegetable [Steck et al. 2007], genistein [Joshi et al. 2007, Metzner et al. 2009],
homocysteine [Yilmaz et al. 2009, Bhupathiraju et al. 2007, De Pergola et al.2001], lignans
[Touillaud et al. 2007], ursolic acid [De Angel et al. 2010]

PRESENT STATE OF ART ON NUTRACEUTICAL MEDICINE IN MENOPAUSE

What we do not know? What can we do?

Although some symptoms are associated with menopause or perimenopause, their cause remains
unclear or we do not know about origin of headache, nausea, joint pain, mood swings, depression,
insomnia, emotional discomfort, changes in sex interest or functioning in menopause. Recent
meta-analysis reports on the success of soy and flax seed as inconclusive further raise doubt. We
have no evidence of biochemical steps altered by phytoestrogens as rate limiting or regulatory
stimulator or inhibitor of estrogen metabolism and cancer pathways having outcome or
consequence to enhance estrogen(s) and killing cancer cells. Author proposed the a nutraceutical
formula with mechanistic approach of bioactive foods and nutraceutical action to improve blood
lipids and cancer prevention but still inconclusive [Sharma et al 2008, 2009, 2010].

For interested readers, I recommend to reinvestigate previous reports and scientific evidences
available but inconclusive now as following:

During early meanopause, breast and ovary cells may indicate following intracellular energy
metabolism alterations but improved by phytoestrogens and herbs and nutraceuticals available in
Herbal-Balance-R®:

 Pyruvate kinase, cytochrome oxidase enzymes: In the presence of oxygen, the mitochondrial
complex I and IV subunits function together as dependent on each other. Possibly, their catalytic
binding with active herb component (nutraceutical like riboflavin, FMN, FAD) provides a
window to measure of estrogen turnover and ovarian/breast cancer cell status, if any. The flavins
and isoflavones might enhance the oxygen utilization by cytochrome oxidase and keep low the
aerobic glucose utilization to generate ATP (substrate level phosphorylation). The enhanced Vmax
and reduced Km value of enzymes for reduction of mitochondrial complexes I and IV are
indicators of mitochondrial function in breast adipocytes or ovarian cells. In cancer cells, in
presence of oxygen, cytochrome oxidase competes with anerobic glucose utilization) and
substrate level phosphorylation to generate ATP. Example: isoflavones and SDG
 Lactate dehydrogenase enzyme: In cancer cells, high LDH enzyme levels (indicator of
anaerobic metabolism) and reduced ratio of equivalents NADH/FADH (during acetyl-CoA
utilization by TCA cycle) indicate the low availability of NADH to electron transport chain in
making ATP. Morin, an anticancer inhibits LDH-V M4. Other example is ubiquinones or CoQ10
 Anaerobic cytosolic carboxylation (TCA cycle status and ETS enzyme battery): Inhibition of
aconitase, isocitrate lyase, malate synthase. Example: blackchoke berry (Hudec et al. 2006)
 High mitogen/stress pathway kinase activity. Example: flavonol, morin [Brown et al.2003]
 Tropoisomerase enzyme inhibition. Example: Frankincense (Boswellia carteri) [Boege et
al.1996]
 p-glycoprotein ATP efflux. Example: flavonoid derivatives[Ikegawa et al. 2002]
 Arrested G2/M, downregulation of NF-kappa B, Akt, cyclin D, c-myc to lead PARP cleavage
and DNA fragmentation. Examples: Vitex, wild yam (Dioscorea villosa) [Shishodia et al.2006]
 Antiproliferation and induced apoptosis (Caspase-3/8/9) and PARP cleavage). Example:
Garcinia cambogia (garcina fruit), Mace [Hostanska et al.2002]
 Blocked leukotriene/5-lipoxygenase pathway inhibition. Example. Hunteria zeylanica
[Reanmongkol et al.1995, Sun et al.2006]
 Garcinia cambogia (garcina fruit) inhibits nuclear histone acetyltransferase p300 and PCAF, as
indicator of pro-apoptosis (beginning or initiation) after cancer cells indicate cell proliferation,
migration, cell adhesion and viability. Other biomarkers are inhibited MAP kinase, ER kinase,
P13K/Akt, membrane adhesion kinase with activated cytochrome C release and PARP-1
cleavage. Example: Garcinol [Liao et al.2005]
 Oxidative stress induced pro-apoptosis: Reduced BCL-2, Bcl-XL and Bid protein by Caspase
3,8 9-OH oxidase, enhanced Bad gene expression and induced DNA fragmentation. Example:
Vitex [Ohyama et al. 2005]
 Downregulation of Cyclin D1 expression/apoptotic effects: Due to reduced proliferation, a
pro-apoptosis process initiates to cause cyclin D1 expression. Example; wild cherry bark.
[Yamagachi et al.2006]
 Expression of gene: Downregulated gene expression of silbinin synthase enzyme causes the
inhibition of breast cancer. Example: JIVA™ [Condori et al.2009]

During onset of menopause or in late stages, anticancer benefits of food supplements are non-
reproducible, unpredictable with individualistic effects in women mainly due to no conclusive
mechanism. I appeal readers to revisit the extent of following benefits with possible scientific
evidences of mechanistic and nutraceutical role with animal models, preclinical and clinical trials
of the following supplements alone or in mixture formula administered in menopause.

 Biochemical mechanisms or pharmacological actions of garlic, acidophilus, flaxseed oil, beet

crystals, kamut grass, bee pollen, alfalfa, anise, barley, carrots, cherries, clover, fennel, garlic,
green beans, hops, licorice, oats, peas, pomegranates potatoes, rice, rye, sesame, sage seeds,
wheat and yeast remain unknown and need extensive investigations
 Ginseng (Panax quinquefolius) shows phytoestrogenic activity in menopause
 Don Quai (herb angelica) improves progesterone metabolism. In menopause, it is
recommended with vitamin E and folic acid
 Dang gui (angelica sinensis) constricts the relaxed uterus and soften a cramping uterus; reduces
atherosclerosis, pain syndrome, spasmodic symptoms
 Vitex or chest berries reduce pain, menopausal distress by stimulating pituitary to produce
progesterone and regular periods
 Black cohosh (Cimicifuga racemosa) shows estrogenic activity, pain reliever, reducing hot
flashes, vasodilatory effect, anti-inflammation, lowering blood pressure, muscle relaxant
 Red clover (Trifolium pretense) herb is high in isoflavones often recommended in menopause
as Promensil® containing 40 mg isoflavones daily
 Siberian ginseng (Eleutherococcus senticosus) increases energy, environmental stress reliever,
reducing fatigue, colds, flus, emotional sensitivity
 Catnip, Chemomile, Passion flower, Lemon balm, Hops, Valerian root, Skullcap reduce
nervous tension and insomnia
 Cooked Rehmannia (Rehmanniae glutinosae), Cornus (Cornus officinalis), Peony (Paeonine
lactiflorae) show replenished blood and essence, relieving from weakness, pain, spasm, cramps,
irritability, mood swings, fatigue, dryness, irregular periods, irregular bleeding, strengthens bones,
sweating, and enhances libido
 Graphites remedy shows relief in night aggravation
 Sepia remedy shows relief in mood swings, pelvic, uterine weakness
 Sabina remedy shows protection against fibroids, abnormal menstruation
 Sanguinaria remedy shows relief in hot flashes
 Sarsaparilla shows relief in hot flashes
 catechins

CRITERIA OF SUGGESTED PRACTICE OF NUTRACEUTICALS IN MENOPAUSE

For early events of menopause, several biomarkers are available such as clinical chemistry tests of
serum glucose, serum homocystein, osteocalcin, cholesterol, blood lipids, hormones, vitamin
receptor genotypes, polymorphisms, thyroid tests, urine excretion of estrogens, bone density, IGF
1α with development of clinical symptoms of hot flash, weight loss, diabetes, hypothyroidism,
breast tenderness as mentioned in the first section on introduction. Preventive
vegetables/foods/green leaves life style, non-meat habits with dietary supplements, bioactive
foods serve well to relieve early menopause symptoms.

For late onset with clear episodes of menopause, regular check-up of clinical evaluation and lab
tests (for DNA damage, apoptosis, estrogenic outcome) to keep the status of menopause progress
in the knowledge of women subject for any need of natural progesterone dose in treatment or
exchange food recommended supplementation to enhance the estrogen synthesis and improving
positive balance of metabolism in bone formation, thyroid regulation, pancreatic glucose
regulation, lipids in cardiovascular system, brain neurotransmitters, ovary estradiol:esterogen
ratio, and oncologic pathways in breast adipocytes. In this stage, vegetable food, green leaves life
style, regular nutraceutical-herbal and natural hormone enhancers prevent the progress of
menopausal episodes while keeping low risk of cancer. In hospitals, to meet expansive hormonal
therapy compliance, physicians recommend overiectomy or hysterectomy. I recommend the safe
use of effective mixture of foods, herbal and nutraceutical supplementation (see next section on
nutraceutical formula) as preventive and therapeutic remedy as long as it is giving benefits till last
stage to keep away breast cancer risk before surgery.
Table 5: The table represents the FDA approved major nutraceuticals with recommended quantity and
sources of nutraceuticals on shelf in super markets. Food and Drug Administration have given guidelines for
recommended daily requirements (RDA) of bioactive foods and its use. Pro-apoptosis Mix® is mixture of
supplements as given in table.

---------------------------------------------------------------------------------------------------------------------

Bioactive component Source Recommended dose

---------------------------------------------------------------------------------------------------------------------
Isothiocyanates broccoli 300 mg/day)
Ubiquinone and derivatives Amaranth 300 mg/day; 3 % wt fraction
Coenzyme Q and derivatives 300 mg/day; 3% wt fraction
Riboflavin and derivatives 300 mg/day; therapeutic dose 1000 mg;
Riboflavin 2’,3,4’,5,7- Pentahydoxyflavone 3% w/v; therapeutic dose 1000 mg)
Polyphenolic Flavonoid 800 mg/day;therapeutic dose 2000 mg; 9% w/w
wt fraction):
2-3 dimethoxy-5-methyl-1,4 benzoquinone therapeutic dose 2000 mg/day; 31% w/w f
Alkaline compounds RDA 750 mg/day; 18% wt fraction)
Antiproliferative bioactive herbs RDA 200 mg/ml; 5% wt fraction
Speranskia or
goldenseal herb powder therapeutic dose 2000 mg)
Balm of Gilead buds,
red sandalwood,
Rosemary therapeutic dose 1500 mg/day; 58% wt
Myrrh gum therapeutic dose 500 mg/day
black walnut therapeutic dose 2000 mg/day, 17% wt
FMN, FAD,
5-amino-6-(5’phosphoribitylamino) uracil,
6,7 Dimetyl-8-(1D-ribityl)lumazine,
ribitol, 5,6-dimethylbenzimidazole therapeutic dose 300 mg/day of each
---------------------------------------------------------------------------------------------------------------------

PHARMACEUTICAL APPROACH OF NUTRACEUTICAL AND HERBAL BALANCE-

R® FORMULA/ PRO-APOPTOSIS MIX® WITH ANTICANCER PROPERTIES IN
MENOPAUSE

The neutraceutical composition is widely advocated in cancer therapy based on combination of

vitamins, salts, roots and herbs prepared in palatable pharmaceutical carrier as neutraceutical
composition described in detail [Sharma et al.2008,2009,2010]. Alternatively herbaceuticals may
be used more efficiently if using in combination with more % of isoflavones and lignans in the
mixture as proposed in this chapter.
A simple plan of menopause relieving HERBAL BALANCE-R® formula is suggested for a blend
of mixture including constituents from selected active biochemicals, herbs, and roots from
following groups 1-4 in cancer prevention for menopausal women:

Group 1: Herb group: (60-90% w/w)

Black cohosh, dong quai or Herbal Balance-F, Ginseng, don quai, dang gui, vitex, black cohosh,
red clover, siberian ginseng, catnip, cooked rehmannia, graphites, sepia, sabina, sanguinaria,
sarsaparilla (up to 60% w/w)

Option of other herbs added (30%): wild yam root (Dioscorea villosa), teasel root (Dipsacus
asper), balm of gilead bud (Populus balsamifera), bakuchi seed (Cymopsis psoralidoides), dichroa
root (Dichroa febrifuga), kochia seed (Kochia scoparia), kantakari (Solanum xanthocarpum),
bushy knotweed rhizome (Polugonum Cuspidatum), arjun (Terminalia arjuna), babul chall bark
(Acacia Arabica), Sweet Myrrh (Opopanax) and bhumy amalaki (Phyllanthus nirur), Garcinia
fruit (Garcinia Cambogia), Vitex (Vitex agnus-castus), Dragons Blood (Calamus draco), Mace
(Myristica fragans), White sage (Salvia apian), red sandal wood (Pterocarpus santalinu)

Group 2: Ubiquinone with precursor: (40-60% w/w)

Vitamin D 10000 units + Calcium citrate 1.5 gm + Magnesium 5 mg + Boron 3 mg added with
2,3 dimethoxy-5-methyl-1,4 benzoquinones (5-45), hydroqunolenes, ubichromenols,
ubichromanols and ubiquinols in form of p-hydroxybenzoate, p-hydroxycinnamate, p-
hydroxyphenylpyruvate, p-hydroxyphenyllactate.(30% w/w)

Group 3: Mitochondrial respiration suppressors: (70-90% w/w)

Biest 2.5 mg, Vitamin C,Vitamin D,Vitamin B mixture + Cr,Cu,Mg,Se,Si,Zn,B,Ca (50%) mixed
with ribitol, riboflavin, flavin adenine dinucleotide, 5-amino-6-(5’-phosphoribitylamino)uracil,
6,7 –Dimethyl-8-(1-D-ribityl)-lumazine, 5, 6-dimethylbenzimidazole with multivitamin mixture.

Group 4: Inhibitor of LDH (60-65% w/w)

2’,3,4’,5,7-pentahydroxyflavone, epigallocatechin galate, quercetin, rosemary (Rosmarinus

officinalis), black walnut (Juglans nigra), clove (Syzygium aromaticum), nutmeg (Myristica
fragans), licorice root (Glycyrrhiza glabra), coriander (Coriandrum sativum), Cinnamon
(Cinnamomum cassia), ginger root (Zingiber officinale), Myrrh gum (Commiphora molmol) and
green tea (Camellia sinensis)

Group 5: alkalinating agent: (15-20% w/w)

aloe vera(Aloe barbadensis), chlorella (Chorella pyrendoidosa), wheat grass (triticum aestivum) in
solution of sodium or potassium carbonate

Group 6: antiproliferative herbs: (5-10% w/w)

Iodine 750 mcg -12.5 mg, Speranskia herb (Speranskia tuberculata) and Goldenseal (hydrastis
Canadensis)

Carrier of different said components in mixture: water, saline, starch, sugar, gel, lipids, waxes,
glycerol, solvents, oils, liquids, proteins, glycols, electrolyte solutions, alcohols, fillers, binders,
emulsifiers, preservatives, buffers, colorants, emollients, sweeteners, surfactants, additives and
solvents used as: solid, liquid, powder, paste, gel, tablet, foam, pack, aerosol, solvent, diluent,
capsule, pill, liposome, syrup, solution, suppository, emulsion, suspension, biodelivery agents.
The nutraceutical mixture may be delivered through oral drops, injectable fluid or external skin
administration for treatment of menopause.

NEW CLINICAL TRIALS OF NUTRACEUTICALS IN MENOPAUSE: YEARS 2004-

2011
In last five years, clinical trials have evidenced the success of phytoestrogens, vitamin, minerals,
herbs, isolated food formulas and diet supplements in several double blind, placebo controlled
studies around the globe. Different studies showed a mix of inconclusive mechanisms but clear
benefits in menopause symptoms including improved bone health, thyroid function and reduced
hot flashes, diabetes, cardiovascular complication with increase in self-esteem, brain health after
individual use of constituent(s) in diet as following:
 S-equol [Oyama et al. 2011, Tousen et al. 2011]
 Vitamin D and calcium[Bolland et al. 2008, 2011, Bertone-Johnson et al. 2011, Tang et al.
2011, Jackson et al. 2011, Millen et al.2010, Lucas et al.2009, LaCroix et al.2009,Di Daniele
et al. 2004]
 Vitamin K with vitamin D[Je et al. 2011, Cheung et al. 2008, Boonen et al.2007]
 Soy isoflavones [NAM study 2011, Levis et al. 2011,Agosta et al. 2011, Choquette et
al.2011, Christe et al. 2004, 2010, Liu et al. 2010, Taku et al. 2010, Li et al. 2010, Liu et
al. 2010, Wong et al.2009, Pop et al.2008, Eisenbrand et al. 2007, Aubertin-Leheudre et
al. 2007, Lindenstuth et al. 2006, Verhoeven et al. 2005, Gann et al. 2005, Kreijkamp-
Kaspers et al. 2004, Chen et al. 2004, ]
 Genistein [Metzner et al. 2009]
 Flax seed lignin [Touillaud et al. 2007, Dodin et al. 2005, 2008, Lewis et al. 2006]
 Glucasamine sulfate [Bruyere et al. 2004]
 Cranberries[Gurley 2011]
 Whey protein [Zhu et al.2011], lactobacilli plus estriol [Donders et al. 2010]
 Sophorus extract[Lee et al. 2010]
 Black cohosh and red clover[Shulman et al. 2011,Newton et al. 2006, Hidalgo et al. 2005
 Folate and one-carbon nutrients[Stevens et al. 2010, Maruti et al. 2010, Stolzenberg-
Soloman et al.2006]
 PUFA[Witt et al. 2010]
 Omega-3 [Lucas et al.2009]
 Cod liver oil [Forsmo et al. 2008]
 Iso-alpha acids, berberine, vitamin K2-D3 trial [Holick et al.2010, Emaus et al.2010]
 Vitamin C and E[Nagel et al. 2010, Rasool et al. 2003]
 Vitamin B2,B12 [Rejnmark et al.2008]
  Citrus foods and potassium citrate [Macdonald et al. 2008]
 L-isoleucine, L-valine [Guttuso et al. 2008]
 Phytofood female and positive behavior life style[Rotem et al.2007, Winzenberg et
al.2006]
 Endothelial dysfunction [Salhotra et al. 2009]

CHALLENGES, HYPES, HOPES AND FUTURISTIC ROLE OF NUTRACEUTICALS

With slow progress and increasing awareness of nutraceutical and herbal benefits in menopause,
common woman in menopause is getting confidence to use them safely and in risk-free manner.
Research investigations are also contributing eye-catching evidences of side-effects of esterogen
hormonal therapy and success or failures of newly introduced or less known potential
phytoestrogens, herbs having anti-cancer effects and their safe use for women in menopause. The
growing hypes of industries and bioactive food-herbal economics put several questions behind
due to lack of scientific evidence before any herbal side effect or ill effects become apparent. Best
example is increased benefits of soy reported in last decade and different opinion now. To avoid
these controversies, governments in developed countries and several regulatory agencies are
playing significant role to monitor the success and efficacy of new or old herbal products in
market. Major focus is now to establish scientific basis with evidence of benefits of
phytoestrogens and food constituents on isolated cells or visualization of effects by imaging or
molecular techniques applied in experimental animals or preclinical women in menopause under
the supervision of nodal NIH,NSF,USDA federal agencies. Presently, we stand at cross road with
following status and future hopes:

 It is continuing process of new phytoestrogens, food constituents and herbs identified,

investigated and researched for their human use under strict supervision and restricting the
marketing strategies regulated by government policies.
 With time, public information will be better and phytoestrogens, diet supplements and
herbs may be considered as therapeutic herbs and effective preventive supplements in
reducing menopause symptoms with no or lesser cancer risk.
 As of today most of the foods, supplements, nutraceuticals and herbs are used by common
woman in menopause based on beneficial effects as word of mouth from friends, relatives
etc. with no knowledge of toxicity or side effects.

Major recommendations are:

 It needs attention sooner before these alternatives become common hazard of menopausal
problems going unnoticed.
 Government marketing policies need to be stringent to make available supplements and
herbs in approved limits of concentration under supervision of nutritionist and food
pharmacy personnel as it is described in this paper.
 Uniform, independent, unbiased acceptable federal policy on the use of phytoestrogens,
supplements and dietary products will be introduced in near future in full compliance with
scientific evidence and clinical trials that will minimize the chances of nutraceutical or
herbal over dosage or diet supplement over intake unrestricted.
CONCLUSION

Phytoestrogen rich foods and nutraceuticals still are growing in number and investigations and
meta analyses suggest high hopes of food supplements in reducing menopause symptoms. Soy
isoflavones, flax seed lignans and vitamins are most widely investigated for benefits in
menopause. However, scientific evidence lack and mechanisms of beneficial effects of
phytosterogens in menopause are still unclear. The role of governments and globalization will
certainly support the documented increasing health risks of estrogen replacement therapy and
positive effects of nutrition supplements in clinical trials. The food supplements and
nutraceuticals are becoming popular as they are harmless and natural food constituents. The
public information of nutrition in menopause in last 5 years demonstrated enormous change in the
perception of nutraceuticals and supplements as preventive and mensopause symptom relieving
non-prescription supplements with no cancer risk in different organs.

Acknowledgements: The information presented in this chapter is intended for professional

education and is obtained from published research, articles, and books. This chapter is not
intended to replace the care of a licensed health professional in the diagnosis and treatment of
illness. Author disclose for any of conflict with any company, industry and academic institution.

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