Background Scientific & Biomedical Information
for fxmenopause
The human oestrogen receptor has two isoforms alpha and beta. Both
isoforms are responsible for mediating the physiological actions of
oestrogens such as estradiol in humans, particularly women. The
oestrogen receptor plays a vital role in many aspects of human biology
such as bone density, collagen synthesis, menstrual cycle, primary and
secondary female phenotypic characteristics such as breast development,
body fat etc. Consequently, either hypo (too low) oestrogen or hyper
(too high) oestrogen levels can contribute to disorders such as
osteoporosis and breast cancer respectively.
Phytoestrogens are naturally occurring compounds from plants that
possess the ability to modulate the human oestrogen receptor isoforms
and consequently exert beneficial biological effects (Murkies et. al,
1998). Phytoestrogens actually refers to a group of polycyclic compounds
that include isoflavones, flavones and lignans that occur naturally in
legumes, fruits and herbs.
The term ‘modulate’ refers to the ability to either augment (enhance) or
attenuate (reduce) activity. For example, if the oestrogen receptors are
saturated with the physiological or synthetic oestrogens (PSE) that
cause hyperactivity, these phytoestrogens may compete with and displace
these PSE. Some phytoestrogens are weaker activators of oestrogen
receptor than PSE and therefore exert a moderating effect on oestrogen
receptor activity. Such effects would be desirable in cases where hyper
levels of oestrogens may pose health risk such as breast and uterine
cancers (Lamartiniere et. al., 2002; Pagliacci et. al.; 1994). On the
other hand, hypogonadal conditions such as menopause which portends
lower oestrogen levels and predisposes the individual to osteoporosis
and other attendant health conditions may benefit from the supplemental
effects of phytoestrogens that help to offset lower levels of
physiological oestrogens in the body (Erdman et. al., 2000). In other
words, phytoestrogens are a class of natural Selective Estrogen Receptor
Modulators (SERMs).
However, different phytoestrogenic plant extracts may contain other
undesirable co-extracted compounds. For example, phytoestrogenic Dong
Quai also contains coumarins, a blood thinner. Black Cohosh besides
having phytoestrogenic effects, also exerts hypotensive effects. In
addition, different classes of phytoestrogens can preferentially
activate the oestrogen receptors isoforms alpha or beta to a different
degree and preliminary scientific research suggest this phenomena may
support the body in distinct aspects such as cardiovascular health,
breast cancer etc (Singer et. al., 2002; Lazennec et. al., 2001).
Therefore, the choice of extracting phytoestrogens from the botanical
source is important.
fxmenopause is a unique dual formulation of two food sourced
phytoestrogens. The bean phytoestrogen has unique SERM activity that
preferentially activates the oestrogen receptor beta to a greater extent
relative to the oestrogen receptor alpha (Please refer to Figure 1).
Figure 1. Selective modulation of the oestrogen receptors (ER) alpha and
beta.
Graph A shows weak agonistic activity of the bean (right striped bar)
relative to the physiological oestrogen, estradiol (middle white bar) on
the ER alpha.
Graph B indicates that the bean (right striped bar) is an efficient
activator of the ER beta with respect to estradiol (middle white bar).
In addition, fxmenopause’s formulation has comprehensive in-vitro
studies that demonstrate its biological ability to synergistically
enhance or boost oestrogen receptors in the presence of their cognate
ligands, the oestrogens (Figure 3).
Figure 2. Synergistic augmentation of oestrogen receptor (ER) in the
presence of its cognate ligand, estradiol.
Phytoestrogens are natural anti-oxidants per se because of their
polycyclic structure. Antioxidants are also incurring a great deal of
interest as emerging data in free oxygen radical research suggests that
cellular and molecular oxidative damage in vivo may play a fundamental
role in the ageing process and associated conditions such as
cardiovascular damage, cancer risk and neurodegenerative diseases.
Dietary phytoestrogens may also support optimal skin condition as human
oestrogen receptors play a role in collagen synthesis and cellular
growth.
fxmenopause is specifically formulated to provide dietary
phytoestrogenic support in adult women only.
The role of fxmenopause in the menopause
years and beyond has been positively assessed by the UK Food Standards
Agency in compliance with regulation EC 1924/2006 relating to nutrition
and health claims made on food. Under this regulation, any food product
claiming to have a health or nutritional benefit is required to be
supported by science and meet a list of European Commission approved
wording.
Preclinical Toxicology Studies
To assess the safety of the components of this product and confirm that it is non-toxic
when consumed, a risk assessment framework was designed according
to the estimated level of exposure. This included acute toxicity,
repeat-dose chronic toxicity and mutagenicity tests. Safety on acute
ingestion has been established based on acute oral toxicity studies.
These studies revealed that the combined botanical extracts did not
cause any significant clinical signs and necropsy findings in doses up
to 2g/kg. No deaths were reported; hence the LD50 could not be
quantified.
Similarly, the extracts did not cause any clinically significant
findings in haematology, blood chemistry, urinalysis or histopathology
of systemic targets in the repeat-dose chronic toxicity studies which
simulate the effects of long term exposure. In addition in genotoxicity
tests, the botanical extracts did not cause any in vivo chromosomal
genetic DNA mutation.
Clinical Efficacy of fxmenopause
In the 2003 UK study on the effects of fxmenopause on menopausal women,
an exposure-response relationship was established. Trial participants
recorded an average 50% and 66% baseline reduction in hot flashes or
night sweats within 10 days and 3 weeks of consumption of fxmenopause,
respectively. The percent reduction is well beyond the 25-30% reduction
usually attributed to placebo. Overall, there was a significant
improvement of total symptom scores measured using the MRS, RAND 36,
PIRS and Facial Skin Questionnaire among the trial participants, leading
to an enhanced quality of life.
References:
Murkies AL, Wilcox G, Davis SR. Clinical review 92: Phytoestrogens. J
Clin Endocrinol Metab 1998 Feb;83(2):297-303.
Lamartiniere CA, Cotroneo MS, Fritz WA, Wang J, Mentor-Marcel R,
Elgavish A. Genistein chemoprevention: timing and mechanisms of action
in murine mammary and prostate. J Nutr 2002 Mar;132(3):552S-558S.
Pagliacci MC, Smacchia M, Migliorati G, Grignani F, Riccardi C,
Nicoletti I. Growth-inhibitory effects of the natural phyto-oestrogen
genistein in MCF-7 human breast cancer cells.Eur J Cancer
1994;30A(11):1675-82.
Erdman JW Jr, Stillman RJ, Boileau RA. Provocative relation between soy
and bone maintenance. Am J Clin Nutr 2000 Sep;72(3):679-80.
Singer CF, Kronsteiner N, Marton E, Walter I, Kubista M, Czerwenka K,
Schreiber M, Tschugguel W, Wieser F, Kubista E. Interleukin-1 system and
sex steroid receptor gene expression in human endometrial cancer.
Gynecol Oncol 2002 Jun;85(3):423-30.
Lazennec G, Bresson D, Lucas A, Chauveau C, Vignon F. ER beta inhibits
proliferation and invasion of breast cancer cells. Endocrinology 2001
Sep; 142(9):4120-30.
1. What are oestrogen receptors and why are they important for women?
Oestrogen receptors are functional proteins in the human body that
detect the presence of female steroid hormones called oestrogens.
They act biologically on many aspects of the woman’s body such as
skin, collagen and connective tissues, breast development,
reproductive functions, bone and muscle metabolism, cardiovascular
and cerebral function, sex drive (libido) and psychological
well-being. Hence, low female hormone (oestrogens) levels can lead
to weak oestrogen receptor action. Lack of oestrogen receptor
activities will then negatively affect many of the above-mentioned
tissues and organs.
2. What are phytoestrogens? ?
Phytoestrogens refer to metabolites found naturally in certain
plants and they are actually a wide range of different compounds
such as isoflavones, lignans and coumarins. These plant metabolites
are NOT steroids but they can still interact with the oestrogen
receptors in the woman’s body. Interestingly, clinical and
scientific studies carried out in Japan, the United States and many
other countries have shown that phytoestrogens interact with the
oestrogen receptors differently from both the human oestrogens and
the synthetic analogues. Phytoestrogens have been suggested to have
a protective effect against some forms of breast cancer, ovarian
cancer etc. Yet at the same time, phytoestrogens can support
cardiovascular function, optimal skin condition and assist in the
relief of hot flushes and other climacteric symptoms.
3. What is the difference between synthetic and physiological
oestrogens, and phytoestrogens?
Both synthetic and physiological oestrogens are steroids. In fact,
17ß estradiol and/or synthetic derivatives containing the
tetracyclic ring system are derived via the mevalonate and
deoxyxylulose phosphate pathways with cholesterol as precursor. On
the other hand, phytoestrogens are derived via the shikimate
pathway. Cinnamic acids precursors lead to lignans. Examples include
enterolactone and enterodiol. Isoflavonoids derived from flavanones
include daidzein and genistein. In other words, phytoestrogens
consists of diverse chemical classes structurally distinct from
steroids.
In terms of biological properties, phytoestrogens such as genistein
have pleotropic effects. For example, genistein not only binds to
the oestrogen receptors (ERs) but is also a competitive inhibitor of
tyrosine kinase (TK). TK is a key signal transduction enzyme
involved in phosphorylation cascade and plays a role in cell growth
and mitosis. Cancer researchers are interested in TK role in
promoting carcinogenesis and metastasis of neoplastic cells. In
contrast, estradiol is not known to be an inhibitor of TK. In fact,
c-fos/c-jun phosphorylation cascade induced by estradiol activation
of ER alpha leads to proliferation of oestrogen sensitive cells.
Oestrogens and phytoestrogens do not share the same chemical nor
biological properties.
4. Do oestrogen receptors exert any side-effects on the human body?
Ostrogen receptors (ERs) are not known to exert side-effects per se
in the human body. Only mutated ERs and/or inappropriate regulation
(hypo or hyper) are implicated in any disorders having ERs as
etiological factors. As further advances in genomics and proteomics
are made, we are increasingly aware of pharmacogenomic differences
between individuals. In other words, optimal oestrogen doses may vary
between patients. 1nM estradiol serum level may be optimal for
individual A but the same dose may lead to over-activation of
individual B’s ERs as individual B may possess a more sensitive
receptor due to polymorphism in her ER encoding gene or even
downstream ER responsive genes.
On the other hand, specific types of phytoestrogens modulate the ER
isoforms differentially. Some phytoestrogens are very weak agonist,
some are strong oestrogen mimetic and some are even natural selective
oestrogen receptor modulators (SERMs) (such as fxmenopause). A weak ER agonist will not adequately suppress climacteric
symptoms but will certainly widen therapeutic index. Hence, the need
for adjuvants that will complement the key pharmacologic compound in
exerting therapeutic relief. A simple oestrogen/progesterone formula
will inevitably fail to achieve this balance. Whereas, a complex
formula, particularly from plants, would permit an array of
molecular pathways to be modulated, thereby allowing for weaker ER
activation that can be compensated via other effectors not involving
the ERs. In other words, not only the ER-based mechanism is
involved, but also anti-inflammatory pathways such as COX-2 and
glucocorticoid receptor (GR) can be harnessed to address the problem
of climacteric vasomotor symptoms such as night sweats and hot
flushes.
5. Is it true that only cognate ligands that can fit spatially into
the tertiary conformational pocket of the apo-LBD of the ERs can
exert an agonist or antagonist effect?
In the old paradigm, only cognate ligands that can fit spatially
into the tertiary conformational pocket of the apo-LBD of the
ERs can exert an agonist or antagonist effect. In the presence
of an agonist binding to the steroid receptor, these PAs will
synergistically enhance the holo-receptor transactivational
function on hormone responsive genes. In hypo-oestrogen
conditions such as menopause; low oestrogen levels or conversely,
weak phytoestrogenic effect can be boosted via the PAs. This
supports ER activity without the need for excessive high doses
of oestrogens or phytoestrogens. This then negates the potential
side-effects associated with high doses of oestrogenic chemicals
(synthetic or plant-based), such as DVT (associated with oestrogen use) or bleeding (associated with some phytoestrogens
such as coumarin). These patents pending phytoaugmenters are
trademarked and are integral components of the
fxmenopause formula.
6. Do both oestrogens or phytoestrogens share the same reported or
anecdotal adverse effects?
Historically and now clinically, oestrogens used in conventional HRT
(cHRT) have been reported to be associated with a myriad of
side-effects such as cancer risks, thrombosis and even
cardiovascular problems. In the same vein, a number of similar
theoretical risks have also been attributed to phytoestrogens (PEs)
and more importantly, vegetative foods containing phytoestrogens on
the assumptions that PEs are oestrogen mimetics. In fact,
epidemiological studies clearly suggest that diets (such as
traditional Japanese or Chinese meals) rich in phytoestrogens
protect against cancers and a host of other chronic diseases.
However, animal studies using isolated or single phytoestrogen such
as genistein at mega-doses have demonstrated that oestrogen-sensitive
tumour growths were increased in vivo and hence the many health
warnings that PEs may be as dangerous as oestrogens used in cHRT. On
the other hand, PEs such as enterolactone and enterodiol have been
implicated in lowering breast cancers amongst vegetarians. A seeming
paradox.
On closer analysis, plants (and hence plant-derived supplements such
as fxmenopause) do not just contain a single type of PE or
even a whole lot of PEs. They (the plants) contain a variety of
other phytochemicals, such as the ones that may be useful in
modulating COX-2 or GR, so on and forth. Specific plants may even
contain indole-3-carbinole (shown in some studies to have
anti-cancer effect) or naturally occurring anti-oxidants which
further contribute to the overall health benefits imparted to the
consumer. Current pharmaceuticals such as ethical drugs used in cHRT
certainly do not provide such adjuvant benefits. Therefore, a
botanical supplement such as fxmenopause, carefully
researched and well formulated using specific plant extracts can
confer both the efficacy required for the specific clinical
condition in question as well as conferring collateral health
benefits.
Clearly, to ignore the various epidemiological studies of Eastern
cultures where cancers and even menopausal symptoms are less
prevalent in PE rich diets vs the recent clinical studies
implicating cHRT in health risks would be closing ourselves to the
benefits that can be derived from botanical therapeutics.
Particularly, ones that are scientifically researched but
selectively formulated from traditional natural remedies such as
fxmenopause.
7. Are hot flushes, mood swings and night sweats due solely to lack
of holo-ER activity?
Vasomotor symptoms such as hot flushes and night sweats plus
psychological disturbances such as mood swings associated with the
climacteric are not due entirely to lack of ER activity. Otherwise,
all postmenopausal women will continue to experience these symptoms.
That is clearly not the case, clinically and anecdotally speaking.
The period of hormonal changes, where oestrogen synthesis is
gradually reduced and the negative feedback mechanism between the
hypothalamus-pituitary-gonadal axis trigger off increased FSH, LH
production plus many other endocrinological changes. These changes
lead to consequent biochemical cascades within the body. These
biochemical processes trigger off associated physiologic
disturbances such pro-inflammatory responses (partially contributing
to hot flushes etc) involving cytokines and prostaglandins etc.
Hence, a botanical supplement such as fxmenopause which
contains specific phytochemicals that can modulate other key
molecular effectors in these perturbed processes (such as COX-2
mediated prostaglandin synthesis) will be able to alleviate the
global menopausal symptoms, without relying on relatively high doses
of oestrogens/oestrogen mimetics (PEs included) that works only via
the ER pathway. Hence, the therapeutic index for an advanced,
scientifically formulated supplement like fxmenopause will be
wider than that of a singular drug entity. On the other hand, many
current health supplements for menopause rely on traditional herbal
information only, but partially using conventional drug development
principle and end up using only a single herbal ingredient (which
again narrows the therapeutic index). Or, using an empirical mixture
of herbs without specific scientifically proven functions, which
does not really differ from the traditional holistic paradigm of
herbal medicines (such as TCM and Ayurvedic).
In contrast, fxmenopause was researched and developed using a
convergence principle, where the fields of molecular genetics,
pharmaceutical technologies and natural remedies are specifically
and selectively converged. This allows fxmenopause to achieve
the broad therapeutic benefits of plant remedies without sacrificing
the cognitive science and technology that underpins modern
mainstream medicine and pharmaceuticals.
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