Note: Descriptions are shown in the official language in which they were submitted.
March 22, 2018 R. Bendera
Title: Composition and Method for Restoring, Regulating and Balancing Male
and Female Hormone Levels
FIELD OF THE INVENTION
The invention is in the field of estrogen dominance and relates to a
composition and method for restoring, regulating, and balancing this disorder.
More
particularly, the invention concerns a composition comprising spermine and/or
spermidine and methods for restoring estrogen hormonal disorders with such
compositions.
BACKGROUND OF THE INVENTION
Researchers have concluded that an overabundance of estrogen is responsible
for a
vast number of today's health problems. This over abundance of estrogen is
referred
to as "estrogen dominance" and is an increasingly serious problem for both
women
and men. Some researchers believe that "estrogen dominance" is the primary
cause
of prostate enlargement and prostate cancer in men and a big risk factor for
breast
cancer in women.
"Estrogen Dominance" can occur during the aging process and can also occur
from
exposure to "estrogen like" substances in the environment known as
"xenoestrogens".
Xenoestrogens are synthetic substances that differ from those produced by
living
organisms and imitate or enhance the effect of estrogens. The estrogenic
stimulation
is an unintended side-effect of these agents or their metabolites.
Xenoestrogens are
part of a heterogeneous group of chemicals that are hormone or endocrine
disruptors. They differ from phytoestrogens (estrogenic substances from
plants),
mycoestrogens (estrogenic substances from fungi), and pharmacological
estrogens
(estrogenic action is intended). External estrogens from a variety of sources
may
have a cumulative effect upon living organisms, and xenoestrogens may be part
of a
larger picture of a process of estrogenization of the environment.
Xenoestrogens
have only been recently (less than 70 years) introduced into the environment,
as
produced by industrial, agricultural, and chemical companies.
Xenoestrogens have been implicated in a variety of medical problems. Foremost
is
the concern that xenoestrogens as false messengers disrupt the process of
reproduction. Studies have implicated observations of disturbances in wildlife
with
estrogenic exposure. Reproductive issues, which are of concern in humans, are
fetal
exposure (perhaps leading to hypospadias) and decreased reproductive ability
in
men (i.e. decrease in sperm numbers). Another issue is the potential effect of
xenoestrogens as oncogenes, specifically in relation to breast cancer.
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Xenostrogen environmental sources includes: commercially raised meat (beef,
chicken and pork), canned foods, plastic food wraps, plastic drinking bottles,
Styrofoam cups, personal care products, cosmetics, birth control pills and
spermicides, detergents, all artificial scents (air fresheners, perfumes,
etc), pesticides
and herbicides, paints, lacquers and solvents.
There are actually three basic estrogens: E3 (estriol), the least powerful and
most
beneficial, comprising 80-90% of human estrogen, E2 (estradiol), the most
powerful
and most carcinogenic, and El (estrone), which has similar properties to
estradiol,
but is considerably less biologically active.
Estrogen Dominance in Men: As men age, their levels of estrogen rise
especially the
two most dangerous and potent estrogens ¨ estrone and estradiol. This
phenomenon is now identified as "andropause". A man over 50 years of age
literally
has more estrogen than his postmenopausal wife. The prostate is
embryologically
the same as the uterus in females: and research studies have shown that like
the
uterus, when prostate cells are exposed to excess estrogen, the cells
proliferate and
become cancerous. In fact it is becoming clear that the excess of estrogen in
aging
men is responsible for a variety of problems such as adiposity, breast
development,
many cancers, prostate problems, baldness and many other problems commonly
associated with advanced age.
Men also produce progesterone, but only about half the amount that females do.
During the aging process progesterone levels in men fall, especially after age
60.
Progesterone is the primary precursor of the male hormone testosterone, which
is an
antagonist to estradiol (E2) and a protector against certain types of cancer.
Progesterone is vital to good health in both men and women.
The concurrent increase of estrogen levels and a decrease of progesterone
levels
creates a very serious hormonal imbalance which is very unhealthy. Either one
of
these hormonal level changes would be bad enough, but both changes occurring
together leads to a vicious cycle,
Because progesterone is the chief inhibitor of an enzyme called 5-alpha
reductase
that is responsible for converting testosterone to dihydrotestosterone (DHT),
when
the level of progesterone falls in men, the amount of conversion from
testosterone to
DHT increases. Increased levels of DHT lead to prostate enlargement and also
an
increased risk of cancer due to the decrease cancer protection that
testosterone
provides.
As the level of DHT increases (and testosterone decreases), the relative level
of
estradiol in men increases. This is compounded by the fact that that there are
inadequate amounts of progesterone there to exhibit it's counteracting effect
of
stimulating the P53 cancer protection gene.
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Like perimenopausal women, men experience a tendency to gain weight in
midlife.
Rising estrogen production can result, since fat cells contain the aromatase
enzyme
that converts testosterone into estrogen. Unmetabolized estrogen creates a
vicious
cycle resulting in further estrogen production. This occurs because fat is one
source
of more active aromatase enzymes, causing further estrogen production and
weight
gain.
Estrogen Dominance in Women: It is common for Women to experience surges of
abnormally high estrogen levels during menopausal and premenopausal periods,
as
well as earlier in life.. It is believed that an excess of estrogen, coupled
with a
deficiency of progesterone ( the counter hormone to estrogen), is the common
denominator for a lot of female troubles.
Some women will develop the estrogen dominance syndrome much later in life,
sometimes as a result of diet, liver impairment, or environmental factors or
also as a
result of anovulatory cycles before menopause ¨ that is, menstrual cycles in
which no
ovulation has occurred. Ovulation is necessary in order to produce the corpus
luteum, ( which means "yellow body" ) that is found on the surface of the
ovary after
ovulation. Surrounding the ripening egg, the corpus luteum remains after
ovulation to
produce progesterone for the last half of the menstrual cycle. Without
ovulation, less
progesterone is produced, which can cause estrogen imbalance in some women.
Diseases or problems that are thought to be related to or effected by excess
estrogen and deficient progesterone in women and men are:
Speeds up the aging process
Allergies
Autoimmune disorders
Breast cancer
Cold hands and feet
Decreased sex drive
Depression
Dry eyes
Infertility
Uterine cancer
Fat gain in abdomen, hips, and thighs
Fatigue
Fibrocystic breast disease
Hair loss
Headaches
Hypoglycemia
Increased blood clotting
Early onset of menstruation
Menstrual disturbances (irregular and heavy bleeding)
Endometriosis (disorder of uterine tissue)
Insomnia
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Foggy thinking and memory loss
Mood swings
Ovarian cysts
Pre-menopausal bone loss
Prostate cancer
Sluggish metabolism
Thyroid dysfunction
Uterine cancer
Uterine fibroids
Water retention and bloating
Consequently, while a variety of treatments have been proposed for treating
estrogen
dominance, none have been entirely successful, and there remains a need for
identifying improved and/or alternative therapies for treating these
disorders. In
particular, improved methods and compositions should be effective and
efficiently
delivered in a non-invasive manner, have minimum side effects and optionally
be
compatible with other hormonal treatments. The instant invention addresses
this
need.
SUMMARY OF THE INVENTION
The present inventors have determined that an effective amount, comprising
spermidine and spermine, is useful in restoring, regulating and balancing
healthy
levels of estrogen.
Accordingly, in one embodiment the present invention provides a composition
for use
in human males, the composition comprising spermine and spermidine in an
amount
effective to restore, regulate and balance normal hormonal levels.
Accordingly, in one embodiment the present invention provides a composition
for use
in human females, the composition comprising spermine and spermidine in an
amount effective to restore, regulate and balance normal hormonal levels.
According to either embodiment it is preferred that the composition is
administered at
least once daily.
In an embodiment of the invention, according to either the method or
composition
where the recipient is a human male or a human female, a preferred composition
of
spermine and spermidine is about 2.5mg of spermine and about 2.5mg of
spermidine.
With respect to components of the composition for the composition and for the
method the spermidine and spermine, they may be derived from green plant
materials, meats and fish, alternatively, the spermidine and spermine may be
synthetically derived.
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Where the source of spermine, spermidine, and vitamin E is from green plants,
such
plants are preferably selected from the group consisting of radish leaves,
corn, oat,
cucumber and other leafy vegetables.
Other features and advantages of the present invention will become apparent
from
the following detailed description. It should be understood, however, that the
detailed
description and the specific examples, while indicating preferred embodiments
of the
invention, are given by way of illustration only, since various changes and
modifications within the spirit and scope of the invention will become
apparent to
those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Spermine and Spermidine are found in virtually every cell in the body. Both of
these
vital polyamines are found in plant, meat and fish sources, with higher levels
of
spermidine found in vegetables and strangely high amounts of spermine being
found
in meats and fish.
A chemical analysis has been performed in respect of corn namely the chemical
constituents of Zea mays L. (Poaceae), cucumber namely the chemical
constituents
of Cucumis sativus L. (Cucurbitaceae), oats namely the chemical constituents
of
Avena sativa L. (Poaceae), and radishes namely the chemical constituents of
Raphanus sativas L. (Brassicaceae) (The Clinicians' Handbook of Natural
Healing by
Gary Null, Kensington Publishing, New York, 1997). Over 90 different chemicals
and
compounds are identified in the list of constituents. The present inventors
have
identified spermine and spermidine as the constituents capable of restoring
balanced
hormonal levels in male and female humans. Spermine and spermidine are both
known as polyamines.
Polyamines are organic cations of low molecular weight which are present in
prokaryotic and eukaryotic cells. The major polyamines in mammals are
putrescine,
spermidine and spermine (Calandra et al. 46:209-222 (1996) Apptla).
Polyamines are ubiquitous chemicals that occur in every living cell. They
fulfil an
array of roles in cellular metabolism and are involved in many steps of
protein, RNA
and DNA synthesis, from the control and initiation of translation to the
regulation of its
fidelity (Dunshea and King, 73:819-828 (1995)). There is a scarcity of
information on
the bioavailability and mechanism of polyamine uptake by the gut and the fate
of
polyamines derived from the gut rumen in humans (Dunshea and King, 73:819-
828).
It appaers that polyamines can be readily taken up from the gut rumen, and it
has
been suggested that this occurs by pass of diffusion (Dunshea and King,73:819-
828).
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Polyamines have different patterns of tissue distribution between mammalian
species
and age and different hormone and environmental conditions will influence the
polyamine pool (Calandra et at. 46:209-222 (1996) Apptla).
Biogenic amines exist naturally in many food stuffs and vegetables such as
Chinese
cabbage, endive, iceberg lettuce, and radishes all of which have been found to
contain varying levels of the aforementioned polyamines. However, changes in
the
biogenic amine content from ungerminated seeds to young plants show a
reduction
in concentration of these polyamines. Further, it is not clear how such
polyamines
could be released from the plants aforementioned.
Both spermine and spermidine, when ingested, are transported from inside the
intestine into the blood stream with only 30% of the ingested amount being
metabolically degraded. Therefore about 70% of what is ingested is
metabolically
available for the body to use in various cellular processes.
Both spermine and spermidine are essential for healthy cell development in the
human body (Merck Index).
Accordingly, the present invention is for a composition comprising spermine
and
spermidine in an amount effective to restore balanced hormonal levels for both
human males and human females with estrogen dominance.
Spermine and spermidine may be the compounds as isolated from corn, cucumber,
oat, and radish leaves and stems, or any other natural source, but also
includes any
portion of the compounds which provides the biological activity of restoring
balanced
hormonal levels in human males and human females who have estrogen
dominance.. Also included in the meaning of the terms spermine and spermidine
are
any and all synthetic analogs of the naturally occurring polyamines, or
biologically
active portions thereof, howsoever prepared.
In another embodiement, the invention provides a method of restoring balanced
hormonal levels in human males and human females with estrogen dominance
comprising administering to the male and female an effective amount of a
composition comprising phytochemicals selected from the group consisting of:
spermine and spermidine.
Spermidine and spermine are derived from green plant materials. Although, it
is
possible to produce synthetic or recombinant spermine, and spermidine, it is
preferably derived from corn, cucumber, oats, lettuce, lentil seeds, radish
leaves,
radish seeds, cabbage, various meats and fish.
"Effective amount", as used herein, is the amount required at dosages and
periods of
time necessary to achieve the specified desired result.
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Dosage Regimes
Where human males and females are the subject, a combined dose that should
produce positive results would be 5mg ¨ 5.4mg of spermine (2.5mg ¨ 2.7mg) and
spermidine (2.5mg ¨ 2.7mg.)
A person skilled in the art, upon reading this description, would appreciate
that the
dosages of the active substances of the compositions of the invention can vary
depending on many factors such as pharmacodynamic characteristics of the
particular substance, and its mode and routes of administration; source of
substance;
age, health, and weight of the patient, nature and extent of symptoms; kind of
current
treatment; frequency of treatment; and the effect desired.
The composition of the present invention when administering spermine and
spermidine, preferably contain suitable pharmaceutical carriers or diluents as
appropriate. Suitable pharmaceutical carriers and methods of preparing
pharmaceutical dosage farms are described in Remington's Pharmaceutical
Sciences Mack Publishing Company, Veterinary Drug Handbook, Donald C. Plum,
University of Minnesota, and Canadian Compendium of Veterinary Products,
Canadian Animal Health Institute, 6th Ed., North American Compendium Ltd.,
Hensal,
Ontario, a standard of reference in this field. Suitable pharmaceutical
diluents,
excipients, or carriers suitably selected with respect to the intended form of
administration, that is, oral tablets, capsules, elixirs, syrups, teas, paste,
and the like,
consistent with conventional pharmaceutical practices. Routes of
administration
include oral, transdermal, and injection by intravenous, intramuscular or
subcutaneous routes. A person skilled in the art would readily ascertain what
a
suitable pharmaceutical carrier would be.
The following non-limiting examples are illustrative of the present invention:
EXAMPLES
Background: The incidence and prevalence of infertility and sexual dysfunction
in
men and women is increasing. The biogenic polyamines spermine and spermidine
are important for sexual function as well as fertility. Spermine and
spermidine are
present in plant foods and synthesized from ornithine and methionine in
mammals.
Stress and stress-associated hormone disruption are contributors to both poor
sexual
function and infertility. Spermine and spermidine are important in reducing
the impact
of stress on living organisms.
Objective / Design: This open-label pilot trial was designed to determine the
impact
of spermine and spermidine supplementation of hormone levels of otherwise
healthy
human subjects with no history of infertility or sexual dysfunction. Pre- and
Post-
supplement levels of Cortisol, DHEAS, Testosterone, Progesterone and Estradiol
as
well as 30-day post supplement levels of these hormones were performed on age
/
gender equivalent subject.
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Results: Clinically significant reductions in Cortisol were seen in 30 days
among
83% of male participants and 37% of female participants. 66% of male
participants
maintained lower cortisol levels 30 days after withdrawal of the study
supplement. In
women, the cumulative effect of the spermine and spermidine supplementation
continued with 50% reporting a significant reduction in cortisol levels 30
days after
withdrawal of the study supplement. There was an average of 3.3 pounds of
weight
loss during the first 30 days of supplementation without any dietary or
metabolic
intervention.
Further, 7 out of 8 female participants demonstrated a moderate increase in
DHEAS
at 30 days, while 5 of 7 male participants demonstrated a significant DHEAS
increase in 60 days. 83% of men had a decrease in estradiol and 100% of men
had
a decrease of progesterone at 30 days while 75% of women in follicular phase
experienced both an increase in estradiol and a significant increase in
progesterone.
In men of the under 50 year age group testosterone levels increased by an
average
of 48.9% (28.3 pg/mL) while in the over 50 age group testosterone levels
decreased
by an average of 36.7% (33pg/mL). In women, 75% had an average increase of
48.8% (10.6 pg/mL) in Testosterone levels at 30 days while the same number
(75%)
had an average decrease of 32.7% (10.5 pg/mL) in Testosterone levels at 60
days.
Conclusion: For both fertility and sexual performance it is important to
reduce
cortisol levels. Also important to fertility is the balancing of various
hormone ratios
during reproductive years. Likewise, it is important for sexual performance of
women
post-menopause and men post-andropause to achieve cortisol reduction and
hormone balance. The biogenic polyamines spermine and spermidine appear to
support a trend toward hormone balance, though a larger trial is needed to
confirm
this conclusion.
The biogenic polyamines spermine and spermidine are ubiquitous in plants since
they are part of prokaryotic and eukaryotic stress response. They are present
in
mammalian tissues as well. In humans and other mammals, spermine and
spermidine are synthesized from the amino acids Ornithine and Methionine.1'3-6
In
2006, Jakszyn and Gonzalez reported that Spermine and spermidine participate
with
nitric oxide synthesis, making spermine and spermidine critical to
reproduction. Salts
of spermine were first isolated in seminal fluid by Leeuwenhoek in 1677.2
Polyamines provided by food seem to be essential for the maintenance of normal
growth and maturation 11'12. Dietary polyamines are associated with cellular
growth
and differentiation. This association was reported to be due to polyamine
interaction
with DNA, RNA, and proteins 3'12. Furthermore, exogenous polyamines modulate
mucosal proliferation and absorption from diet13. Hence, insufficient
polyamine intake
could hinder important health enhancing effects of polyamines such as
induction of
tolerance to dietary allergens14. A high intake of spermine is associated with
a
decreased risk of food allergy among suckling rats as well as in children, due
to the
contribution of spermine to maturation of both the immune system 4,16 and the
small
intestinal mucosa 16.
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Dietary polyamines provide both antioxidant and anti-inflammatory properties
7'18.
The antioxidant activity of polyamines has been shown to be even stronger than
that
of some antioxidant vitamins 18.
Cortisol: Glucocorticoids, primarily cortisol, are produced by the adrenal
glands in
response to stressors such as emotional upheaval, exercise, surgery, illness
or
starvation. In response to a stressor, most organisms have an automatic
reaction that
engages the mechanisms necessary for mobilization. This response,
automatically
activated as a defense against any threat, is designed to provide the energy
resources necessary for survival and to shut down all unnecessary functions,
such as
digestive and reproductive functions. Consequently, in order for an organism
to
engage in sexual activity, the stress response would need to be inactive.
Cortisol plays an essential role in the stress response. Although there are a
series of
autonomic and endocrine responses that occur when an organism is faced with a
stressor, cortisol has become commonly known as "the stress hormone."
Cortisol's
role in the endocrine system is metabolic, and it is released both after
eating and in
response to stressful situations. As part of the stress response, cortisol
acts on
various metabolic pathways to provide energy where it is needed in the body
during a
stressful fight or flight situation. Although increased cortisol release is
not the only
marker of the stress response, measuring cortisol response is a simple way to
make
a reasonable judgment about whether or not an organism is experiencing a
stress
response. This is particularly useful in sexual arousal studies because
cortisol is only
active in specific instances, whereas, for example, the sympathetic nervous
system is
activated in a variety of situations including both sexual arousal and during
stress.19-21
Cortisol is made from progesterone. (Table 1) In situations where there is
excessive
cortisol production and release in response to stress, progesterone levels
decline.
This happens because cortisol is much more necessary for life than
progesterone,
therefore progesterone gets converted into cortisol. Since cortisol and
progesterone
compete for common receptors in the cells, cortisol impairs progesterone
activity,
setting the stage for estrogen dominance. Without adequate progesterone, a
fertilized egg will not be maintained in the uterus. According to the American
Society
for Reproductive Medicine, infertility affects about 10% of men and women of
childbearing age. Chronically elevated cortisol levels can be a direct cause.
In this study, 83% of men and 37% of women experienced a significant reduction
in
cortisol during the 30-day supplementation with spermine and spermidine. Once
the
supplement was withdrawn the levels of cortisol began to rise among men but
continued to decline among women, reaching 50% after an additional 30 days.
(Table 2, 3)
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.......' -1
1,01-o
Prep..loae -... 17e OH Pregneoolone -. DHEA
1,11.5D I ',mu.
1 , . . . 1 raw 1 1 P4i" GONADS
------------------------- _1
ADRENAL CORTEX
Table 1
MALE
Cortisol Dif 1/2 Dif 2/3 Dif
1/3
2 pg/mL % pg/mL % pg/mL %
00261 24.0 7.3 7.6 9.1 -0.3 4.1 -1.5 19.7 -1.8
24.7%
00694 <30 6.4 3.0 3.2 3.4 -53.1 -0.2 6.6 3.2
-50.0%
00753 52.4 8.1 7.1 12.5 1.0 -12.3 -5.4 76.1 -4.4
54.3%
01129 >50 5.6 2.8 1.2 2.8 -50.0 1.6 -57.1 4.4
-78.6%
01239 61.4 8.2 4.4 18.3 3.8 -46.3 -13.9 315.9 -10.1
123.1%
01386 53.8 8.2 0.9 3.8 7.3 -89.0 -2.9 322.0 4.4
-53.7%
01596 <30 10.8 *** 4.4 *** *** Irk* *** 6.4
-59.3%
Table 2 3.7 -50.1 4.6
-60%
'
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FEMALE
Cortisol Dif 1/2 Dif 2/3 Dif
1/3
2 pg/mL % = s/mL % =
./mL %
00158 44.6 9.6 9.9 6.7 -0.3 3.1% 3.2 32.3% 2.9
30.2%
00337 25.2 6.0 7.1 13.1 -1.1 18.3% -6.0 84.5% -7.1
118.3%
00439 25.10 3.5 1.9 1.0 1.6 -45.7% 0.9 -47.4% 2.5
-71.4%
00543 52.10 10.7 0.8 0.8 9.9 -92.5% 0.0 0.0% 9.9
-92.5%
00819 18.2 7.9 8.9 9.1 -1.0 12.7% -0.2 2.2% -1.2
15.2%
00921 <30 6.1 2.3 1.8 3.8 -62.3% 0.5 -21.7% 4.3
-70.5%
01034 <30 2.0 4.3 3.4 -2.3 114.9% 0.9 -20.9% -1.4
70.0%
01412 36.3 6.1 8.4 14.0 -2.3 37.7% -5.6 66.6% -7.9
129.5%
5.1 -66.8% 4.9
-51.1%
Table 3
DHEAS: DHEA, or dihydroepiandrosterone, is one of the major steroid hormones
produced by the adrenal glands, and sometimes by the gonads (ovaries and
testes).
The body converts DHEA into male and female sex hormones, such as estrogen and
testosterone. When a sulfate group (special molecule containing a sulfur atom
and
four oxygen atoms), it forms DHEAS (dihydroepiandrosterone sulfate). Most DHEA
is
found as DHEAS in the blood. Women with infertility and men with erectile
dysfunction frequently have low levels of DHEAS.
In this study, 71% of men at 60 days and 37% of women at 30 days experienced a
significant elevation in DHEAS following 30 day supplementation with spermine
and
spermidine. (Table 4,5)
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MALE
DHEAS Dif 1/2 Dif 2/3
Dif 1/3
2 pg/mL % pg/mL % pg/mL %
00261 24.0 8.7 14.3 10.4 -5.6 64.4 3.9 -27.3 -
1.7 19.5
_
00694 <30 42.2 3.9 9.8 38.3 -90.8 -5.9 151.3
32.4 -76.8
00753 52.4 5.1 4.0 4.5 1.1 -21.6 -0.5 12.5 0.6
-11.8
01129 >50 10.1 5.9 4.5 4.2 -41.6 1.4 -23.7
5.6 -55.4
01239 61.4 3.6 2.8 4.2 0.8 -22.2 -1.4 50.0 -0.6
16.7
01386 53.8 6.9 1.5 5.3 5.4 -78.3 -3.8 253.3 1.6
-23.2
01596 <30 19.1 *** 23.8 .===== =-=-= *** =-k=
4.7 24.6
Avg
Decrease: 10.0
Avg Increase:
8.9
Table 4
FEMALE
DHEAS Dif 1/2 Dif 2/3
Dif 1/3
2 = ./mL % pg/mL %
pg/mL %
00158 44.6 4.4 5.5 7.2 -1.1 24.9% -1.7 30.9% -
2.8 63.6%
00337 25.2 12.2 13.0 9.5 -0.8 6.5% 3.5 -26.9%
2.7 -22.1 A
00439 25.10 1.3 1.4 0.7 -0.1 7.7% 0.7 -50.0%
0.6 -46.2 A
00543 52.10 5.2 2.8 3.5 2.4 -46.2% -0.7 25.0% 1.7
-32.7 A
00819 18.2 6.7 7.5 8.8 -0.8 11.9% -1.3 17.3% -
2.1 31.3%
00921 <30 7.6 8.8 5.6 -1.2 15.8% 3.2 -36.4%
2.0 -26.3 A
01034 <30 9.5 20.7 12.5 -11.2 117.9% 8.2 -39.6% -
3.0 31.6%
01412 36.3 13.2 16.2 11.1 -3.0 22.7% 5.1 -31.5%
2.1 -15.9 A
Avg
Increase: -2.6
Avg Decrease: 4.1
1.9
Table 5
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Testosterone: Testosterone is the primary sex hormone in the male body.
However,
it is also present and needed in the female body for the same process, just in
lesser
quantities. Testosterone is responsible for the changes that come on around
puberty
in men such as the voice lowering, enlargement of the penis and testes and
hair
growth. It is also the key hormone behind the male libido, or the desire to
have sex.
In women, it is largely responsible for enhancing the female libido and sexual
function. Testosterone can be made in three different places. For men, most of
the
testosterone is made in the testicles. For men and women, small amounts of
testosterone can be made by the adrenal glands. For women only, small amounts
can also be made in the ovaries.
Testosterone productions starts with signals that are transported from the
pituitary
gland and the hypothalamus. The hypothalamus produces a hormone called
gonadotropin. This hormone transmits to the pituitary gland, which is then
stimulated
to produce follicle-stimulating hormones. These hormones run from the
pituitary
gland to the testicles and tell the testes to produce testosterone. The brain
is then
able to sense when the body has enough or too much testosterone and regulate
its
production through the pituitary gland.
Elevated cortisol associated with stress may cause a shortage of testosterone
in the
body. Not getting enough testosterone for men can mean a decreased sex drive
and
erectile dysfunction. In women, it can result in a lowered libido.
In this study, men under age 50 experienced a 48.9% testosterone increase
women
experienced a 48.8% testosterone increase during the 30-day supplementation
with
spermine and spermidine. (Table 6, 7)
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MALE
Testosterone Dif 1/2 Dif 2/3 Dif
1/3
2 pg/mL % pg/mL % pg/mL %
00261 24.0 72.0 92.0 100.0 -20.0 27.7 8.0 8.7
28.0 38.8
00694 <30 55.0 52.0 101.0 3.0 -5.5 49.0 94.2
46.0 83.6
00753 52.4 62.0 65.0 56.0 -3.0 4.8 9.0 -13.8
6.0 -9.7
01129 >50 75.0 50.0 35.0 25.0 -33.3 15.0 -30.0
40.0 -53.3
01239 61.4 88.0 58.0 59.0 30.0 -34.1 -1.0 1.7
29.0 -32.9
01386 53.8 105.0 31.0 52.0 74.0 -70.5 -21.0 67.7
53.0 -50.5
01596 <30 45.0 *** 56.0 *** *** *** *ft
11.0 24.4
Avg
Decrease: 33.0 36.7%
Avg Increase:
28.3 48.9%
In the 24-30 yr age group testosterone levels increased by an average of 48.9%
(28.3
pg/mL)
(increase from 11-46
pg/mL)
In the >30 age group testosterone levels decreased by an average of 36.7%
(33pg/mL)
(decrease from 3-74
pg/mL)
Table 6
CA 2998921 2018-03-22
FEMALE
Testosterone Dif 1/2 Dif 2/3 Dif
1/3
2 = eirriL % pg/mL %
pg/mL %
00158 44.6 34.0 39.0 31.0 -5.0 14.7% 8.0 -20.5% 3.0
-8.8%
00337 25.2 26.0 40.0 34.0 -14.0 53.8% 6.0 -15.0% -8.0
30.8%
00439 25.10 18.0 27.0 13.0 -9.0 50.0% 14.0 -51.9% 5.0
-27.7%
00543 52.10 36.0 16.0 12.0 20.0 -55.5% 4.0 -25.0% 24.0
-66.6%
00819 18.2 31.0 38.0 39.0 -7.0 22.6% -1.0 2.6% -
8.0 25.8%
00921 <30 46.0 39.0 22.0 7.0 -15.2% 17.0 -43.6% 24.0
-52.1%
01034 <30 17.0 35.0 21.0 -18.0 105.8% 14.0 -40.0% -4.0
23.5%
01412 36.3 24.0 35.0 35.0 -11.0 45.8% 0.0 0.0% -
11.0 45.8%
Avg
Increase: 10.6 48.8% __
Avg Decrease: 10.5 32.7%
Table 7
CA 2998921 2018-03-22
Progesterone: Progesterone is secreted by the empty egg follicle after
ovulation has
occurred, known as the corpus luteum. It is highest during the last phases of
the
menstrual cycle, after ovulation. Progesterone causes the endometrium to
secrete
special proteins to prepare it for the implantation of a fertilized egg. When
fertilization
does not occur, it prevents the body from creating and releasing more eggs in
the
later stages of the menstrual cycle.
If conception has occurred, progesterone becomes the major hormone supporting
pregnancy, with many important functions. It is responsible for the growth and
maintenance of the endometrium. It also suppresses further maturation of eggs
by
preventing release of LH and FSH (Follicle Stimulating Hormone). By relaxing
the
major muscle of the uterus, progesterone prevents early contractions and
birth. It
does, however, also thicken the muscle helping the body prepare for the hard
work of
labor. Finally, progesterone suppresses prolactin (the primary hormone of milk
production), preventing lactation until birth.
Progesterone is a female hormone used for reproduction but it is also found in
men.
While progesterone still largely functions as a female reproduction
facilitator, it can
also be beneficial to men suffering from benign prostatic hyperplasia or an
enlarged
prostate. Men produce about half as much progesterone as women. They use it to
make testosterone, the main male hormone, and produce cortisone, a hormone
produced by the adrenal glands. (Table 1)
The prostate is a gland a little larger than a walnut that wraps around the
urethra just
under the bladder. It helps the fertilization process by producing a fluid
filled with
nutrients that mixes with the sperm to form semen and helps the sperm survive
in the
vagina's environment. The prostate experiences a growth spurt from male
puberty to
about the age of 20. It begins to grow again during a man's 40s as a natural
part of
aging. This is called benign prostatic hyperplasia and most men will have it
by their
50s and 60s.
Men produce both testosterone and estrogen, another female hormone. The ratio
of
testosterone to estrogen is very high in a healthy man, but as men age that
ratio can
change. Many scientists believe that this is what causes the growth of the
prostate as
men age. Progesterone counteracts the effects of estrogen in men and improves
the
testosterone/estrogen ratios. It prevents testosterone from being converted
into DHT,
a weaker version of testosterone that dilutes the male hormone ratio.
In this study, 100% of men achieved an average decrease of 11.0 pg/mL (46.3%)
in
Progesterone levels at 30 days and 85.7% maintained an average decrease of
10.0
pg/mL (37.2%) in Progesterone levels at 60 days. 100% of women with a decrease
of progesterone levels at 30 days were either post-menopausal or in the luteal
phase
of the menstrual cycle. These levels remained lower than baseline at 60 days.
On
average Progesterone levels decreased 22.8 pg/mL. However, 100% of women with
an increase of Progesterone levels at 30 days were in the follicular phase of
menstruation. These levels remained higher than baseline at 60days. On
average,
Progesterone levels increased 32.0 pg/mL.
CA 2998921 2018-03-22
MALE
Pro = esterone Dif 1/2 Dif 2/3 Dif
1/3
2 pg/mL % pg/mL %
../mL %
00261 24.0 22.0 18.0 13.0 4.0 -18.2 5.0 -27.7 9.0
-40.9
00694 <30 20.0 9.0 19.0 .11.0 -55.0 10.0 111.1
1.0 -5.0
00753 52.4 16.0 12.0 15.0 4.0 -25.0 3.0 25.0 1.0
-6.3
01129 >50 33.0 12.0 7.0 21.0 -63.6 5.0 -41.6 26.0
-78.8
01239 61.4 21.0 5.0 26.0 16.0 -76.2 21.0 420.0 -
5.0 23.8
01386 53.8 25.0 15.0 15.0 10.0 -40.0 0.0 0.0 10.0
-40.0
01596 <30 25.0 *ft 12.0 1,-** *** *** ***
13.0 -52.0
AVG Decrease
pg/mL 11.0 -46.3
10.0
-37.2
Table 8
FEMALE
Pro = esterone Dif 1/2 Dif 2/3 Dif
1/3
2 pg/mL % pg/mL % =
./mL %
57.0 132.0 110.0
00158 44.6 -75.0 131.6% 22.0 16.6% -
53.0 92.9%
0 52.0 42.0 35.
00337 25.2 10.0 -19.2% 7.0 16.6%
17.0 -32.7%
00439 25.10 21.0 72.0 83.0 -51.0 242.9% -11.0 15.3% -
62.0 295.2%
00543 52.10 37.0 8.0 11.0 29.0 -78.4% -3.0 37.5%
26.0 -70.3%
0 23.0 21.0 14.
00819 18.2 2.0 -8.7% 7.0 33.3% 9.0
-39.1%
00921 <30 48.0 9.0 9.0 39.0 81.2% 0.0 0.0% 39.0
81.2%
0 38.0 49.0 44.
01034 <30 -11.0 38.9% 5.0 10.2% -
6.0 15.8%
01412 36.3 16.0 16.0 23.0 0.0 0.0% -7.0 43.8% -
7.0 43.8%
AVG Decrease 20.0 -6.3%
22.8 __
AVG Increase -45.7 137.8% -
32.0 111.9%
Table 9
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Estradiol: Estradiol is the form of estrogen produced by the ovary, and is
what is
measured during routine infertility monitoring.
Estrogen is a group of hormones that are known best for their role in changing
a girl
into a woman with child-bearing potential. Estrogen also helps regulate the
menstrual
cycle, protects bones from thinning, and keeps cholesterol levels low to
protect the
heart. Estrogen can sometimes help turn normal breast tissue into cancers.
Estrogen
is made in three ways: within your body, in nature, and in a synthetic form
used in
medications.
Estrogen, like any other hormone, can be both beneficial and harmful. Research
has
shown that a few chemicals, called estrogenic xenobiotics, can mimic estrogen
in the
body and cause health problems the same way that excessive estrogen might do
naturally. For example, the chemical nonylphenol, found in cleaning products,
paints,
herbicides, and pesticides, can damage human sperm.
Many medicinal and edible plants contain compounds called phytoestrogens,
which
are chemically similar to the sex hormone estradiol, the primary estrogen in
humans.
Although it's generally regarded as a "woman's hormone," estradiol also occurs
naturally in a man's body (it's produced in the testes). In addition, as in a
woman's
body, a man's body produces precursor hormones (including testosterone), which
are converted to estradiol. (Table 1) In a man's body, estradiol is involved
in sexual
functioning, the synthesis of bone, cognitive functioning, and the modulation
of
several diseases (including cancer and heart disease).
In this study, 83% of men experienced a 55.9% decrease in Estradiol in 30
days.
This indicates that spermine and spermidine may be potent estrogen-blocking
supplements. 50% of women experienced an increase in Estradiol during the 30-
day
supplementation with spermine and spermidine, 75% of these also experiencing a
concomitant increase in Progesterone. Once the supplement was withdrawn the
levels of Estradiol began to decline among women and increase in men. (Table
10,
11)
CA 2998921 2018-03-22
MALE
Estradiol Dif 1/2 Dif 2/3
Dif 1/3
Number AGE YY.M 2 = ./mL % pg/mL %
pg/mL %
00261 24.0 2.4 1.0 1.0 1.4 -58.3 0.0 0.0
1.4 -58
00694 <30 1.7 0.5 2.7 1.2 -70.6 2.2 440.0
-1.0 58.1
00753 52.4 1.2 0.8 1.5 0.4 -33.3 0.7 87.5
-0.3 25.1
01129 >50 3.3 7.7 34 -4.4 133.3 4.3 -55.8
-0.1 3.0
01239 61.4 1.2 0.5 0.8 0.7 -58.3 0.3 60.0
0.4 -33
01386 53.8 1.7 0.7 1.8 1.0 -58.8 1.1 157.1
-0.1 5.9
01596 <30 1.6 *** 1.5 *** **-k *** inkie
0.1 -6.:.:
Avg
Decrease: 0.9 55.9% 1.1
Avg Increase:
0.4 32.1
Table 10
CA 2998921 2018-03-22
FEMALE
Estradiol Dif 1/2 Dif 2/3
Dif 1/3
Number AGE YY.M 2 = s/mL % pg/mL %
= ./mL %
00158 44.6 1.7 2.9 1.6 -1.2 70.6% 1.3 -44.8%
0.1 -5.E
3.5 2.5 2.9
00337 25.2 1.0 -28.6% -0.4 15.9%
0.6 17.=
00439 25.10 0.8 1.1 1.4 -0.3 37.5% -0.3 27.3% -
0.6 74.!
1.3 0.6 0.8
00543 52.10 0.7 -53.8% -0.2 33.3%
0.5 38.!
1.7 0.9 0.6
00819 18.2 0.8 -47.0% 0.3 -33.3%
1.1 64."
3.1 3.4 2.0
00921 <30 -0.3 9.7% 1.4 -41.2%
1.1 35.!
2.4 3.1 1.9
01034 <30 -0.7 29.2% 1.2 -38.7%
0.5 20.1
1.7 1.5 1.5
01412 36.3 0.2 -11.8% 0.0 0.0%
0.2 11.1
Avg
Increase: 0.6 36.8%
Avg Decrease:
0.6 27."
Table 11
CA 2998921 2018-03-22
Conclusion: Spermine and spermidine, the biogenic polyamines found in food and
produced endogenously from the amino acids ornithine and methionine, reduce
cortisol levels in men and women, opening the way for improved sexual function
and
fertility. Further, they decrease estradiol in men, potentially negating some
of the loss
of sexual function associated with estrogen dominance. Spermine and spermidine
improve the estrogen levels in some women and also improve the estrogen to
progesterone ratio, again, potentially reducing the negative effects of
estrogen
dominance. Spermine and spermidine improve testosterone levels in men under
age
50 and increase DHEAS levels in men over age 50, both markers correlated with
improved sexual function.
Women who experienced non-disabling mood swings and irritability associated
with
hormone fluctuations demonstrated a significant reduction in symptoms (80%)
after
only 30 days on spermine / spermidine supplementation. Further, women who
experience low back and hip pain associated with hormone fluctuations
demonstrated a significant reduction in symptoms (80%) after only 30 days on
spermine / spermidine supplementation. Men likewise experienced reduction in
pain
or fatigue in the legs or back (62%).
Men experiencing low energy level or stamina realized a 50% improvement in
symptoms and women experiencing unusual fatigue realized a 75% improvement in
symptoms after only 30 days on spermine / spermidine supplementation.
Finally, among men experiencing a sense of bladder fullness and frequent or
urgent
need to urinate, fully 55% demonstrated a significant reduction in symptoms
after
only 30 days on spermine / spermidine supplementation. Women experiencing
urinary difficulties found their symptoms we relieved (66%) after only 30 days
on
spermine / spermidine supplementation.
Claims:
1. Increased Cortisol levels are associated with reduced sexual function and
fertility. Supplementation with Spermine and Spermidine reduced cortisol
levels by 50% to 83% in 30 to 60 days.
2. Increased Testosterone levels are associated with improved sexual
function in men and women. Supplementation with Spermine and
Spermidine increased Testosterone levels in Women and in Men under
age 50 by 49%.
3. Increased DHEA levels are associated with improved sexual function in
men and women. DHEA was increased by 83% in men at 60 days of
supplementation with Spermine and Spermidine and 87% in women in
only 30 days of supplementation.
4. Increased Estradiol in Men is associated with reduced sexual function and
feminization (e.g. gynecomastia or breast enlargement). Most men
experienced a 55% reduction in Estradiol with only 30 days of
supplementation with Spermine and Spermidine.
5. Decreased levels of Estradiol in Women is associated with reduced sexual
function. Supplementation with Spermine and Spermidine increased
Estradiol levels in women by 37% in 30 days.
CA 2998921 2018-03-22
6. Decreased Progesterone level in Women is associated with infertility, poor
sexual function and rapid aging of the skin. Progesterone levels increased
by 32 pg/mL in women of childbearing age with only 30 days of
supplementation with Spermine and Spermidine.
7. Increased Progesterone level in Men is associated with poor sexual
function. After 30 days of supplementation with Spermine and Spermidine,
100% of men experienced a significant reduction in their level of
Progesterone.
8. Women with imbalanced hormones typically experience fatigue, irritability
and pain in the hips and low back. Most women in our study found relief
with 30 days of Spermine and Spermidine supplementation.
9. Men with imbalanced hormones typically experience fatigue and pain in
the low back. Most men in our study found relief with 30 days of Spermine
and Spermidine supplementation.
10. Men and women with imbalanced hormones typically experience urinary
difficulties of various types. Most men and women in our study found relief
with 30 days of Spermine and Spermidine supplementation.
CA 2998921 2018-03-22
DISCUSSION
The foregoing examples illustrate that a composition of the present invention
including spermine and spermidine can result in an overall improved
estrogen/hormonal balance in both male and female humans resolving estrogen
dominance. As indicated in the data provided in Example 3, an increase in the
numbers of individuals tested should provide more significant results.
Furthermore,
these examples have been conducted at only a few dosage ranges based on body
weight. As will be understood by those skilled in the art, variations in the
ranges will
provide optimum results.
As will be readily appreciated the advantages of using the compounds spermine
and spermidine in a composition for administration for ease of preparation,
accuracy
of dosing, stability, enhanced shelf life, and ease and stability in
transportation and
delivery.
While the present invention has been described with references to what are
presently considered to be preferred examples, it is to be understood that the
invention is not limited to the disclosed examples. To the contrary, the
invention is
intended to cover various modifications and equivalent arrangements included
within the spirit and scope of the appended claims.
All publications, patents and patent applications are herein incorporated by
reference in their entirety to the same extent as if each individual
publication, patent,
or patent application was specifically and individually indicated to be
incorporated by
reference in its entirety.
CA 2998921 2018-03-22
FULL CITATIONS FOR REFERENCES REFERRED TO IN THE SPECIFICATION
1. Groppa & Benevides, 2008
2. ROLE OF POLYAMINES IN REPRODUCTIVE PHYSIOLOGY AND SEX
HORMONE ACTIONtH. G. Williams
3. Bardocz S, Duguid TJ, Brown DS, Grant G, Pusztai A, White A, et al. The
importance of dietary polyamines in cell regeneration and growth. Br J Nutr.
1995;73:819-28.
4. Loser C. Polyamines in human and animal milk. Br J Nutr. 2000;84:S55-8.
5. Tabor CW, Tabor H. Polyamines. Annu Rev Biochem. 1984;53:749-90.
6. Loser C, Folsch UR. Importance of various intracellular regulatory
mechanisms of polyamine metabolism in camostate-induced pancreatic
growth in rats. Digestion. 1993;54:213-23.
7. Bardocz S. Polyamines in food and their consequences for food quality and
human health. Trends Food Sci Technol. 1995;6:341-6.
8. Eliassen KA, Reistad R, Risoen U, Ronning HF. Dietary polyamines. Food
Chem. 2002;78:273-80.
9. Larque E, Sabater-Molina M, Zamora S. Biological significance of dietary
polyamines. Nutrition (New York, NY, United States) 2007;23:87-95.
10. Deloyer P, Peulen 0, Dandrifosse G. Dietary polyamines and non-neoplastic
growth and disease. Eur J Gastroenterol Hepatol. 2001;13:1027-32.
11. Loser C, Eisel A, Harms D, Folsch UR. Dietary polyamines are essential
luminal growth factors for small intestinal and colonic mucosal growth and
development. Gut. 1999;44:12-6.
12. Canellakis ZN, Marsh LL, Bondy PK. Polyamines and their derivatives as
modulators in growth and differentiation. Yale J Biol Med. 1989;62:481-91.
13. Seidel ER, Scemama JL. Gastrointestinal polyamines and regulation of
mucosal growth and function. J Nutr Biochem. 1997;8:104-11.
14. Kalac P, Krausova P. A review of dietary polyamines: formation,
implications
for growth and health and occurrence in foods. Food Chem. 2004;90:219-30.
15. Dandrifosse G, Peulen 0, El Khefif N, Deloyer P, Dandrifosse AC, Grandfils
C. Are milk polyamines preventive agents against food allergy? Proc Nutr
Soc. 2000;59:81-6.
16. Dufour C, Dandrifosse G, Forget P, Vermesse F, Romain N, Lepoint P.
Spermine and spermidine induce intestinal maturation in the rat.
Gastroenterology. 1988;95:112-6.
17. lgarashi K, Kashiwagi K. Polyamines: mysterious modulators of cellular
functions. Biochem Biophys Res Commun. 2000;271:559-64.
18. Lovaas E, Carlin G. Spermine: an anti-oxidant and anti-inflammatory agent.
Free Radic Biol Med. 1991;11:455-61.
19. Exton MS, Bindert A, Kruger T, Scheller F, Hartmann U, Schedlowki M.
CA 2998921 2018-03-22
Cardiovascular and endocrine alterations after masturbation-induced orgasm
in women. Psychosom Med 1999;61:280-9.
20. Exton NG, Truong TC, Exton MS,Wingenfeld SA, Leygraf N, Sailer B,
Hartmann U, Schedlowski M. Neuroendocrine response to film-induced
sexual arousal in men and women. Psychoneuroendocrinology 2000;25:187-
99.
21. Heiman JR, Rowland DL, Hatch JP, Gladue BA. Psychophysiological and
endocrine responses to sexual arousal in women. Arch Sex Behav
1991;20:171-86.
We Claim:
1. The present inventors have determined that an effective amount,
comprising
spermidine and spermine, is useful in restoring, regulating and balancing
healthy levels of estrogen.
2. Accordingly, in one embodiment the present invention provides a
composition
for use in human males, the composition comprising spermine and spermidine
in an amount effective to restore, regulate and balance normal hormonal
levels..
3. Accordingly, in one embodiment the present invention provides a
composition
for use in human females, the composition comprising spermine and
spermidine in an amount effective to restore, regulate and balance normal
hormonal levels.
4. According to either embodiment, it is preferred that the composition is
administered at least once daily.
5. In an embodiment of the invention, according to either the method or
composition where the recipient is a human male or a human female, a
preferred composition of spermine and spermidine is about 2.5mg of
spermine and about 2.5mg of spermidine.
6. With respect to components of the composition for the composition and
for the
method the spermidine and spermine,they may be derived from green plant
materials, meats and fish, alternatively the spermidine and spermine may be
synthetically derived.
7. Where the source of spermine, spermidine, and vitamin E is from green
CA 2998921 2018-03-22
Other
plants,ther f esautcuhr eplants d are advantages preferably of
t h the
selectedpres present
rnotm the invention groupw i l consisting obnesciosmt i neg apparent
radish
leaves, corn, oat, cucumber and other leafy vegetables.
8.
from the following detailed description. It should be understood, however,
that
the detailed description and the specific examples while indicating preferred
embodiments of the invention are given by way of illustration only, since
various changes and modifications within the spirit and scope of the invention
will become apparent to those skilled in the art from this detailed
description.
CA 2998921 2018-03-22
