CA2998921A1 - Composition and method for restoring, regulating and balancing male and female hormone levels - Google Patents

Description

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.

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.

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 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.

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).

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.

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.

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.

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) .......' -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

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%
' FEMALE
Cortisol Dif 1/2 Dif 2/3 Dif 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) 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 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) MALE
Testosterone Dif 1/2 Dif 2/3 Dif 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 FEMALE
Testosterone Dif 1/2 Dif 2/3 Dif 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 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.

MALE
Pro = esterone Dif 1/2 Dif 2/3 Dif 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 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 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) 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 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 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.

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.

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.

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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 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.