Compositions and treatments for reducing potential unwanted side effects associated with long-term administration of androgenic testosterone precursors

A method for reducing potential adverse effects of androgenic testosterone precursors by interfering with production or action of testosterone and estrogen metabolites by nutrient combinations is described. Although androgenic testosterone precursors themselves have little or no toxicity, there is the potential for their metabolites, estradiol and dihydrotestosterone, to enhance or cause hormone-responsive illnesses such as breast or prostatic cancer, benign prostatic hyperplasia, or hirsutism or acne in women. The use of the invented nutrient combinations reduces the formation or action of estradiol and dihydrotestosterone, thereby reducing potential adverse effects from increased production of these hormones following androgenic testosterone precursor administration. This may be accomplished without negating the effects of testosterone on muscle anabolism. The nutrient combinations include androstenedione, DHEA, pregnenolone, androstenediols, norandrostenedione and norandrostenediols, and natural products which reduce estrogen effects in the estrogen-responsive tissues, and substances to reduce formation of dihydrotestosterone from testosterone in prostate tissue.

BACKGROUND OF THE INVENTION 
A. Field of the Invention 
The invention relates to the use of nutrient combinations to prevent or 
reduce potential adverse effects from administration of androgenic 
testosterone precursors to humans and other mammals Specifically, the 
invention relates to co-administration of androgenic testosterone 
precursors such as pregnenolone, androstenediols, norandrostenediols, 
norandrostenedione, androstenedione or dehydroepiandrosterone in 
combination with natural products which inhibit estrogen effects in liver, 
adipose, prostate, ovarian, uterine, breast and other estrogen-responsive 
tissues, and substances which inhibit the production of 
dihydrotestosterone in prostate tissue. 
B. Description of Related Art 
Androstenedione (.DELTA..sup.4 -androstene-3,17-dione) is an adrenal 
steroid hormone. Pregnenolone is a precursor for dehydroepiandrosterone. 
Dehydroepiandrosterone (DHEA) is a precursor of androstenedione. 
Androstenedione is a direct precursor of estrone and testosterone in 
target tissues that possess the appropriate receptors and enzymes. 
Androstenediols are direct precursors for testosterone after oral 
administration in adult humans (unpublished data). 19-Norandrostenedione 
is a precursor for 19-nortestosterone, which has anabolic actions similar 
to testosterone, with less androgenic actions. 19-Norandrostenedione is a 
potential precursor for estrone. Testosterone is important for the 
development and maintenance of male sexual organs and characteristics, 
behavioral effects, anabolic (growth-promoting) actions, and metabolic 
effects for all tissues, especially muscles, liver and kidney. (Kutsky, R. 
J., Handbook of Vitamins, Minerals and Hormones, 2.sup.nd ed., Van 
Nostrand Reinhold Company, New York, 1981). Estrogens are essential for 
the development and maintenance of female reproductive organs and 
characteristics, pregnancy, and metabolic effects for all tissues (Kutsky, 
1981). 
Androstenedione levels in tissues, including skeletal muscle, of men and 
women decrease significantly with age. (Deslypere, J. P. and Vermeulen, 
A., Influence of age on steroid concentrations in skin and striated muscle 
in women and in cardiac muscle and lung tissue in men, J. Clin. 
Endocrinol. Metab. 61:648-653 (1985)). Since muscle wasting is associated 
with aging, these findings suggest that the loss of androstenedione is 
involved in muscle wasting. The corollary that androstenedione 
administration would maintain muscle mass is enticing, but has not been 
studied yet. Nevertheless, the data support an anabolic effect of 
androstenedione on muscle tissue in both men and women, with more 
effectiveness in men. 
Blood levels of androstenedione decrease in some young men during 
prolonged, intense exercise. This decrease is thought to impede 
performance improvements. For example, serum androstenedione levels 
declined as weightlifting intensity increased in young men. (Alen et al., 
Responses of serum androgenic-anabolic and catabolic hormones to prolonged 
strength training, Int. J Sports Med. 9:229-233 (1988)). While 
androstenedione and other androgens were decreased, serum testosterone was 
maintained, which suggests that androstenedione provides precursors for 
synthesis of testosterone by muscle. Other indicators of over-training 
were more apparent as androstenedione levels decreased. Thus, 
androstenedione supplementation to young men engaged in vigorous weight 
training may help prevent androstenedione deficiency, and maintain 
anabolic responses to weight training. 
To counteract this decrease in androstenedione levels, athletes have taken 
androstenedione orally, nasally or intravenously to increase testosterone 
levels. Empirical research supports the link between the administration of 
androstenedione and increases in testosterone levels. For example, oral 
and nasal administration of androstenedione to women increases serum 
testosterone levels. (Maresh, V. B. and Greenblatt, R. B., The in vivo 
conversion of dehydroepiandrosterone and androstenedione to testosterone 
in the human. Acta Endocrinol. 41:400-406 (1962); Mattern, C. and Hacker, 
R., European Patent Application No. 97-13 0639077 (1977)). Furthermore, 
androstenedione is converted into testosterone in muscle and adipose 
tissue in humans after intravenous administration. (Belisle et al, 
Metabolism of androstenedione in human pregnancy: use of constant infusion 
of unlabeled steroid to assess its metabolic clearance rate, its 
production rate, and its conversion into androgens and estrogens, Am. J. 
Obstet. Gynecol. 136: 1030-1035 (1980); Longcope, C. and Fineberg, S. E., 
Production and metabolism of dihydrotestosterone in peripheral tissues, J. 
Steroid Biochem. 23:415-419 (1985)). (This reference, and all the other 
references in this and subsequent sections, are incorporated by reference 
in their entirety.) These data have generated interest in androgenic 
testosterone precursors as ergogenic aids for improving anabolism in 
exercising persons, especially weight lifters and bodybuilders. Dietary 
supplement products containing androstenedione, androstenediols, 
norandrostenedione and norandrostenediols alone or in combination with 
other ingredients have appeared on the market recently. 
Evidence has accumulated that suggests androstenedione excess is not 
benign. Androstenedione affects hormonally responsive target tissue in 
males and females. Androstenedione administration may cause overproduction 
of estradiol from estrone, and dihydrotestosterone (DHT) from 
testosterone. Estradiol and DHT account for most of the hormonal effects 
of estrogens and testosterone in target tissues. For example, long-term 
treatment of dogs and monkeys with androstenedione causes prostate 
enlargement and temporary shrinkage of testicles. While dogs are more 
sensitive to estrogens than humans, side effects may also occur in humans. 
Such side effects may include breast and prostatic cancer, benign 
prostatic hyperplasia, and hirsutism or acne in women. Since DHEA is a 
metabolic precursor of androstenedione, DHEA administration may also be 
associated with harmful side effects. Thus, androstenedione and DHEA 
administration should be carefully monitored to provide the desired 
anabolic effects without causing harmful side effects. 
There is insufficient evidence to assess side effects from 
norandrostenediols or norandrostenedione from animal or human scientific 
literature. However, the known metabolic pathways of these prohormones 
indicate that estrone, in amounts equivalent to those formed by 
androstenedione or testosterone, can be formed from nor- analogs of 
androstenedione and testosterone (Raeside, J. I., Renaud, R. L., and 
Friendship, R. M., Aromatization of 19-norandrogens by porcine Leydig 
cells. J Steroid Biochem. 32(5):729-735 (1989)). These results indicate 
that the potential for unwanted side effects with nor-prohormones may be 
equivalent to that for androstenedione and testosterone. 
Thus, there is a need for a composition and method for minimizing or 
preventing unwanted side effects associated with the administration of 
androgenic testosterone precursors in humans. In particular, there is a 
need for a composition and method which maintains androgenic testosterone 
precursor levels while minimizing or eliminating the effects of estrogen 
and DHT excess. 
SUMMARY AND OBJECTS OF THE INVENTION 
The present invention provides a safe and effective composition of, and 
method for administering, androgenic testosterone precursors which promote 
anabolic metabolism while inhibiting unwanted side effects Those side 
effects result from the metabolism of prohormones into byproducts which 
cause such side effects. The present invention combines novel ingredients 
to limit the effects of these metabolic byproducts without interfering 
with the beneficial effects of androgenic testosterone precursor 
administration. Specifically, the invented composition includes components 
which reduce or prevent the unwanted side effects of androgenic 
testosterone precursor administration in hormone responsive-tissues 
without inhibiting anabolic effects in muscle. 
The composition of the present invention includes androgenic testosterone 
precursors such as pregnenolone, androstenedione, dehydroepiandrosterone 
(DHEA), androstenediols, norandrostenedione, and/or norandrostenediols in 
combination with one or more natural products for inhibiting estrogen 
effects in liver, adipose, prostate, ovarian, uterine, breast and other 
tissues responsive to estrogen (hereafter "anti-estrogen activity"). The 
composition further includes one or more substances for preventing the 
production of dihydrotestosterone (DHT) in prostate tissue (hereafter 
"anti-DHT activity"). 
Natural products with anti-estrogen activity include catechin polyphenols, 
tocotrienols, isoflavones and similar flavonoid compounds such as citrus 
flavonoids and saponin flavones, phytosterols, resorcyclic acid lactones, 
indoles, saponins, glucarates and guaianolides from Asteraceae species. 
Substances with anti-DHT-activity include zinc salts, Saw Palmetto berry 
(Serenoa repens), Pygeum africanum, and green tea (Camellia sinensis). 
Natural products with anti-estrogen activity and substances with anti-DHT 
activity may further include whole herbs or plants, parts thereof, powders 
thereof, and semi-purified extracts as well as purified extracts. 
It is an object of the present invention to provide a composition of, and 
method for administering, androgenic testosterone precursor(s) which 
promotes anabolic responses during exercise while minimizing unwanted side 
effects. 
It is another object of the present invention to provide a composition of, 
and method for administering, androgenic testosterone precursor(s) and a 
natural product(s) which promote anabolic responses to exercise while 
inhibiting estrogen effects in the liver, adipose, prostate, ovarian, 
uterine, breast and other tissues responsive to estrogen. 
It is a further object of the present invention to provide a composition 
of, and method for administering, androgenic testosterone precursor(s) and 
a substance(s) with an anti-DHT activity to promote anabolic responses 
during exercise while inhibiting unwanted side effects caused by the 
overproduction of DHT from testosterone. 
It is still another object of the present invention to provide a 
composition of, and method for administering, androgenic testosterone 
precursor(s) which prevents overdosing of androgenic testosterone 
precursors. 
It is still another object of the present invention to provide a 
composition of, and method for administering, androgenic testosterone 
precursor(s) which promotes anabolic metabolism while maintaining 
androgenic testosterone precursors, testosterone, DHT, DHEA sulfate and 
other hormones within normal physiological ranges. 
It is a further object of the invention to provide a composition of, and 
method for, administering androgenic testosterone precursors which spares 
normal hormones levels from depletion due to overtraining. 
These and other objects, features and advantages of the invention will be 
clear to a person of ordinary skill in the art upon reading this 
specification in light of the appending drawing.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
Referring to FIG. 1, the invented composition is intended to be taken as an 
oral dosage form. The invented composition includes at least one 
androgenic testosterone precursor such as pregnenolone, androstenedione, 
DHEA, androstenediols, norandrostenedione, norandrostenediols, and analogs 
thereof, in combination with one or more natural products having an 
anti-estrogen activity and one or more substances having an anti-DHT 
activity. The ingredients of the present invention lend themselves to the 
incorporation into, and the production of, nutritional supplements which 
are especially useful as orally-administrable dosage forms including, but 
not limited to, capsules, tablets, bars, gums, candies, powders, drinks, 
liquid sprays and liposomal solutions (hereafter "oral dosage forms"). 
A. Description of the Ingredients 
Androgenic Testosterone Precursors--The invented composition includes 
metabolic precursors of estrogen and testosterone such as pregnenolone, 
androstenedione (.DELTA..sup.4 -androstene-3,17-dione), 
dehydroepiandrosterone (DHEA), .DELTA..sup.4 
-androstene-3.beta.,17.beta.-diol (4-androstenediol), .DELTA..sup.5 
-androstene-3.beta.,17.beta.-diol (5-androstenediol), 
19-norandrost-4-ene-3,17-dione (19-norandrostene-dione), and 
19-norandrost-4 or 5-ene-3.beta.,17.beta.-diol (norandrostenediols). 
Analogs of these androgenic testosterone precursors which are estrogen or 
testosterone precursors are also within the scope of the present 
invention. These androgenic testosterone precursors are available from 
commercial sources such as Technical Sourcing International, Inc. and 
Sigma Aldrich Fine Chemicals. Methods of preparing androstenedione and its 
analogs are disclosed in U.S. Pat. Nos. 4,100,026, 4,100,027, 4,474,701, 
5,418,145, and 5,516,649. Each of these patents is incorporated by 
reference in its entirety. 
Natural products containing anti-estrogen activity--The natural products 
with an anti-estrogen activity reduce or inhibit estrogen effects in 
estrogen-responsive tissues. Such natural products act by blocking 
estrogen receptors in estrogen-responsive tissues or by effecting the 
removal and/or destruction of estrogen in the body. Estrogen-responsive 
tissues include liver, adipose, prostate, ovarian, uterine, and breast 
tissues. 
The natural products may include, but are not limited to, catechin 
polyphenols, tocotrienols, isoflavones and similar flavonoid compounds 
such as citrus flavonoids and saponin flavones, phytosterols, resorcyclic 
acid lactones, indoles, saponins, glucarates and guaianolides from 
Asteraceae species. For example, catechin polyphenols, bioflavonoids, 
indoles and saponins in green tea, soy and other plants are effective in 
blocking estrogen receptors in prostate tissue. Glucarates, tocotrienols 
and indole-3-carbinol stimulate the removal of estrogen from the body. 
Biochanin A and 7,8-benzoflavone are effective in blocking estrogen 
receptor-binding sites and reducing aromatase activity. Guaianolides from 
Asteraceae species also inhibit aromatase activity. 
Herbs and plants, and extracts therefrom, which have such anti-estrogen 
activity, are also within the scope of the invention. Natural products 
containing catechin polyphenols include green tea, black tea and catechu. 
Preferred natural products containing tocotrienols include rice bran, rice 
bran oil, and red palm oil. The preferred sources of isoflavones and 
bioflavonoids include soybeans, pulses, soy germ, bee propolis, alfalfa, 
cloves, and citrus fruits such as oranges. Other flavonoid-rich herbs, 
plants, foodstuffs and purified compounds from flavonoid-rich herbs, 
plants and foodstuffs are also within the scope of the present invention. 
Preferred sources of phytosterols include alfalfa, soy extracts and red 
clover. Preferred sources of indoles include broccoli extracts and 
synthetic sources. Finally, the preferred sources of saponins include soy. 
The preferred glucarates include calcium-D-glucarate, potassium hydrogen 
D-glucarate, glucaric acid, D-glucaro-1,4-lactone and 
pharmaceutically-acceptable salts thereof. 
Other natural products are within the scope of the present invention if 
they are effective in blocking the binding of estrogen to estrogen 
receptors, or in increasing the removal or destruction of estrogen in the 
body without inhibiting the estrogenic pathway in muscle. Assays to 
measure such activity are well-known to those of skill in the art. For 
example, receptor binding assays may be conducted according to the method 
of J. L. Witliff and E. D. Savlov (Estrogen-binding capacity of 
cytoplasmic forms of the estrogen receptors in human breast cancer, in 
Estrogen Receptors in Human Breast Cancer, W. L. McGuire, P. P. Carbone 
and E. P. Vollmer, eds, Raven Press, New York (1975), pp.73-86), which is 
incorporated by reference herein. Briefly, extracts are prepared from 
frozen tissue samples (e.g., breast tissue) by immersion in liquid 
nitrogen, and then shattered to form a powder. The powder is homogenized 
in ice cold 10 mM Tris-HCl, 1.5 mM EDTA, 250 mM sucrose, pH 7.4, to form 
the extract. Protein concentrations may be adjusted according to standard 
methods. 
The inhibition of estrogen-receptor binding may be measured by sucrose 
gradient assay, as disclosed in Witliff and Savlov (1975). Briefly, tissue 
aliquots, which are prepared as described above, are incubated with 
radiolabeled estrogen and varying amounts of a natural product or extract 
therefrom. After incubation is complete, the amount of radiolabeled 
estrogen is determined in control and experimental samples after 
separation of the free estrogen from bound estrogen. To separate free from 
bound estrogen, the incubation mixture is mixed with dextran-coated 
charcoal, centrifuged at 1,000.times.g for 10 minutes at 3.degree. C. and 
then further centrifuged on a linear sucrose gradient (5-40%) for 15-17 
hours at about 308,000.times.g. After centrifugation, each gradient is 
fractionated and the amount of radioactivity in each fraction determined 
with a scintillation counter. The dextran-coated charcoal procedure of 
Wittliff and Savlov (1975) is an alternate procedure for the determination 
of estrogen receptor binding. Another preferred assay for 
estrogen-receptor binding is the luciferase whole cell assay described in 
Lobaccaro et al. (Steroidal affinity labels of the estrogen receptor. 3. 
Estradiol 11.beta.-n-alkyl derivatives bearing a terminal electrophilic 
group: Anti-estrogenic and cytotoxic properties, J. Med. Chem. 40:2217-27 
(1997)), which is incorporated herein by reference. 
To identify natural products which affect the removal or destruction of 
estrogen from the body, blood serum assays may be used. For example, a 
radiolabeled estrogen is infused into a subject mammal followed by the 
infusion of unlabeled androstenedione. Whole blood samples are 
periodically withdrawn and the metabolic clearance rate of the infused 
radiolabeled estrogen is measured. By comparing the clearance rates in 
control and experimental subjects provided with natural products, the 
efficacy of those products may be readily determined. An example of a 
metabolic clearance rate determination for androstenedione, DHEA, 
testosterone, estrone and estradiol is disclosed in Belisle et al. (The 
metabolism of androstenedione in human pregnancy; The use of constant 
infusion of unlabeled steroid to assess its metabolic clearance rate, its 
production rate, and its conversion to androgens and estrogens, Am. J 
Obstet. Gynecol., 136: 1030-1035 (1980)), which is incorporation by 
reference herein. Anti-estrone antibodies are available from Steran 
Research Ltd. (London, England). The quantitation of androstenedione and 
estrogen levels in serum have been performed by RIA, as described in Resko 
et al. (Sex steroids in the umbilical circulation of fetal rhesus monkeys 
from the time of gonadal differentiation, J. Clin. Endocrinol. Metab 
50:900-905 (1980)), and Belisle et al. (The effect of constant infusion of 
unlabeled dehydroepiandrosterone sulfate on maternal plasma androgens and 
estrogens, J. Clin. Endocrinol. Metab. 45:544-550 (1977)), which are 
incorporated by reference herein. Methods for radioactive, enzymatic and 
colorimetric quantitation of antigen levels are generally disclosed in 
Harlow, E. and Lane, D., Antibodies: A Laboratory Manual (Cold Spring 
Harbor, 1988), which is incorporated by reference herein. 
Substance with anti-DHT activity--The substance with anti-DHT activity 
inhibits the conversion of testosterone to dihydrotestosterone. Substances 
having anti-DHT activity include zinc salts such as the acetate, 
alaninate, alpha-aminobutyrate, arginate, ascorbate, benzoate, butyrate, 
beta-hydroxybutyrate, n-butyrate, carnosinate, chloride, citrate, formate, 
glycinate, gluconate, histidinate, iso-leucinate, iso-valinate, leucinate, 
lysinate, monomethionate, oxide, picolinate, propionate, succinate, 
sulfate, transferrin, and valinate forms. The zinc salt is preferably a 
pharmaceutically acceptable form, as will be appreciated by those of skill 
in the art. Other substances with anti-DHT activity include Saw palmetto 
berry (Serenoa repens) powders and extracts, Pygeum africanum powders and 
extracts, green tea powders and extracts containing epicatechin gallete 
esters, pumpkin seeds oils and powders, beta-sitosterol, and 
calcium-D-glucarate. In a more preferred embodiment of the invention, the 
substance with anti-DHT activity is a zinc salt, including but not limited 
to, zinc arginate, citrate, acetate, chloride, sulfate, picolinate, oxide 
and monomethionate. 
The ability of substances to inhibit DHT production may be conveniently 
determined by measuring the conversion of radiolabeled testosterone to DHT 
in cell extracts or tissue homogenates. Such assays are preferably 
conducted using extracts from prostate tissue or from prostate tissue 
culture cells. The preparation of tissue homogenates and the measurement 
of the conversion of radiolabeled testosterone to DHT are described in 
articles by J. P. Deslypere and A. Vermeulen (Influence of age on steroid 
concentration in skin and striated muscle in women and in cardiac muscle 
and lung tissue in men, J. Clin. Endocrinology Metab. 61: 648-53 (1985)), 
J. P. Deslypere and A. Vermeulen (Aging and tissue androgens, J. Clin. 
Endocrinology Metab. 53: 430-34 (1981)) and J. P. Deslypere et al. 
(Androgen concentrations in sexual and non-sexual skin as well as in 
striated muscle in man, J. Steroid Biochem. 13: 1455-58 (1980)), which are 
incorporated by reference herein for the disclosed methodologies. Steroids 
are extracted from the homogenates by precipitation of the protein with 
acetone, the acetone is evaporated from the aqueous phase, the aqueous 
phase is extracted with ether and the residue defatted with 70% methanol. 
After evaporation of the methanol, the aqueous phase is extracted with 
dichloromethane. Testosterone and DHT are separated by paper 
chromatography in a Bush B3 system. To further separate testosterone from 
other comigrating compounds such as androstenedione, the products may be 
separated by column chromatography using Sephadex LH20. DHT may be further 
separated from androstenedione by thin layer chromatography on an Al.sub.2 
O.sub.3 support with a 3:1:1 (v/v) benzene/chloroform/ethylacetate system. 
RIA procedures have been described in Deslypere and Vermeulen (1981) and 
Deslypere et al. (1980), which are incorporated by reference for the 
disclosed procedures and sources of antibody. 
B. Composition of the Invention 
The ingredients of the invention are readily available commercially or may 
be synthesized according to known methods. The androgenic testosterone 
precursors, natural products with anti-estrogen activity, and substances 
with anti-DHT activity are preferably of food-grade quality or better. 
Pharmaceutically-acceptable salts of these ingredients are also within the 
scope of the present invention. When amounts are specified as weight 
percentages, those percentages are based on the total weight of androgenic 
testosterone precursor, natural product with anti-estrogen activity, and 
substance with anti-DHT activity. 
For androstenedione, the therapeutically effective dosage level can range 
from about 1 mg to about 1,000 milligrams per day. In a more preferred 
embodiment, the effective dosage ranges from about 25 to about 250 
milligrams per day. In the most preferred embodiment of the invention, the 
dosage is about 100 milligrams per day. These dosages are for persons 
within a weight range of about 50 to about 110 kilograms. These ranges may 
proportionately adjusted for persons or greater of lesser weights. For 
androstenedione analogs, the effective dosage is determined by normalizing 
the analog's activity to that of androstenedione. 
For DHEA, the therapeutically effective dosage level can range from about 1 
mg to about 1600 milligrams per day. In a more preferred embodiment, the 
effective dosage ranges from about 5 to about 100 milligrams per day. In 
the most preferred embodiment of the invention, the dosage is about 25 
milligrams per day. In another preferred embodiment, the DHEA dosage is in 
excess of 30 milligrams per day. As for androstenedione, these dosage 
ranges may be proportionally adjusted for persons outside the weight range 
of about 50 to about 110 kilograms. For DHEA analogs, the effective dosage 
is determined by normalizing the analog's activity to that of DHEA. 
For androstenediols, the therapeutically effective dosage level can range 
from about 1 mg to about 1500 milligrams per day. In a more preferred 
embodiment, the effective dosage ranges from about 5 to about 150 
milligrams per day. In another more preferred embodiment, the effective 
dosage ranges from greater than 30 to about 150 milligrams per day. In the 
most preferred embodiment of the invention, the dosage is about 100 
milligrams per day. As for androstenedione, these dosage ranges may be 
proportionally adjusted for persons outside the weight range of about 50 
to about 110 kilograms. For androstenediol analogs, the effective dosage 
is determined by normalizing the analog's activity to that of 
androstenediol. 
For pregnenolone, norandrostenediols and norandrostenedione, the 
therapeutically effective dosages can range from about 1 mg to about 1000 
milligrams per day. In a more preferred embodiment, the effective dosages 
may range from about 5 to about 150 milligrams per day. In the most 
preferred embodiment, the amount of pregnenolone is about 100 milligrams 
per day. These dosage ranges may be proportionally adjusted for persons 
outside the weight range of about 50 to about 110 kilograms. For analogs 
of pregnenolone, norandrostenediols, and norandrostenedione, the effective 
dosage is determined by normalizing the analog's activity to that of 
pregnenolone, the norandrostenediol or norandrostenedione, respectively. 
The therapeutically effective dosage range for the purified or partially 
purified natural product(s) with anti-estrogen activity may range from 
about 1 to about 75 weight percent. In a more preferred embodiment of the 
invention, the effective range is from about 10 to about 50 weight 
percent. In the most preferred embodiment, the effective dosage is about 
20 weight percent. For crude extracts or herb or plant parts, the 
effective dosage levels may range from about 10 to about 70 weight 
percent. In a more preferred embodiment, the effective dosage levels may 
range from about 20 to about 50 weight percent. In the most preferred 
embodiment, the effective dosage is about 30 weight percent. 
The therapeutically effective dosage range of the substance with anti-DHT 
activity is from about 1 to about 75 weight percent. In a more preferred 
embodiment, the effective dosage amount may range from about 10 to about 
50 weight percent. In the most preferred embodiment, the amount is about 
20 weight percent. 
When the substance with anti-DHT activity is zinc, the effective dosage 
range of elemental zinc may range from about 1 to about 250 mg. In a more 
preferred embodiment, the effective dosage ranges from about 5 to about 
150 milligrams. In the most preferred embodiment, the amount of anti-DHT 
activity is about 10 mg. For zinc salts, the effective ranges may be 
calculated by normalizing the amount of zinc in the zinc salt to that of 
elemental zinc. 
In a more preferred embodiment of the invention for women, the substance 
with anti-DHT activity may be omitted from the composition. In such a 
composition for women, the relative amounts of androgenic testosterone 
precursor and natural product with anti-estrogen activity are as disclosed 
above, except that the relative weight percentages are based on the total 
weight of androgenic testosterone precursor and natural product with 
anti-estrogen activity. 
The present invention may further include flavorings and colorings to 
increase consumer appeal and to mask any unpleasant tastes of the 
composition. This is particularly true for androstenedione, which has a 
bitter taste. 
The present invention may beneficially also be admixed with various 
pharmaceutically suitable, inactive excipients, carriers, diluents, 
lubricants and adjuvants and then formed into capsules and tablets, as 
will be appreciated by those of ordinary skill in the art. Examples of 
inactive excipients, carriers, diluents, lubricants, disintegrants 
include, but are not limited to, the following: cellulose, substituted 
cellulose, calcium carbonate, dicalcium phosphate, starches, lactose, 
modified food starches, dextrose, calcium sulfate, magnesium carbonate, 
magnesium stearate, stearic acid, glycerin, vegetable oils, polysorbates, 
lecithin, silicon dioxide (silica), food glaze, talc, croscarmellose 
sodium, povidone, water and gelatin. Additional inactive excipients, 
carriers, diluents, lubricants and adjuvants which may be used with the 
invented composition are disclosed in the Handbook of Food Additives (CRC 
Press), which is incorporated by reference herein in relevant part. 
(Pharmaceutically suitable, inactive excipients, carriers, diluents, 
lubricants, adjuvants and disintegrants are hereafter termed 
"pharmaceutically suitable carriers.") 
For capsules or tablets, the amount of the composition per oral dosage may 
be varied according to the preferred size of the capsule or tablet. For 
capsules, the total amount of the composition may range from about 1 mg to 
about 2000 mg, although greater or lesser amounts are within the scope of 
the invention. For tablets, the total amount of composition may range from 
about 10 mg to about 2000 milligrams, although greater or lesser amounts 
are within the scope of the invention. For bars, gums, candies, sprays, 
powders and drinks, the invented composition may be mixed with inactive 
ingredients, colorings and flavorings to achieve the preferred dosage, as 
will be appreciated by those of skill in the art. 
C. Method of Making Oral Dosage Forms 
The invented composition is intended to be taken orally. In addition to 
tablets and capsules, other equivalent oral dosage forms are within the 
scope of the invention, as will be readily appreciated by those of skill 
in the art. Methods of forming capsules, tablets and powders by wet or dry 
granulation, are well-known in the art. Suitable procedures for making 
oral dosage forms are described in Pharmaceutical Dosage Forms and Drug 
Delivery Systems, 6.sup.th Ed. (H. C. Ansel, N. G. Popovich and L. V. 
Allen, Eds., Williams & Wilkins (1995)), which is incorporated by 
reference herein. Other suitable procedures are disclosed in 
Pharmaceutical Dosage Forms: Disperse Systems, Vol. 2, 2.sup.nd Ed. (H. A. 
Lieberman, L. Lachman and J. B. Schwartz, Eds. (1996)), and Pharmaceutical 
Dosage Forms: Tablets, Vols. 2 and 3, 2.sup.nd Ed. (H. A. Lieberman, L. 
Lachman and J. B. Schwartz (1990)), which are incorporated by reference 
herein. In the most preferred embodiment of the invention, the composition 
is manufactured according to good manufacturing practices, as disclosed in 
21 C.F.R., part 110 and quality tested according to US Pharmacopia, 
23.sup.rd Ed., both of which are incorporated by reference herein. 
D. Method of Using the Invented Composition 
The composition of the present invention may be taken one or more times per 
day. In the most preferred embodiment of the invention, the recommended 
dosage of androstenedione and DHEA should preferably not exceed 150 and 
250 milligrams per day, respectively, to avoid potentially harmful side 
effects. If more than one dosage per day is desirable, then the 
composition may be mixed with inert ingredients and divided into the 
desired number of proportionate doses, as will be appreciated by those of 
skill in the art. 
In the most preferred embodiment of the present invention, the anti-DHT 
activity includes a zinc salt. Zinc salts act as an emetic above certain 
dosage levels. For example, dosages of zinc sulfate above about 150 
milligrams per day cause emesis. Thus, taking an overdose of androgenic 
testosterone precursors may be prevented through controlling zinc levels 
in the invented composition, as will be appreciated by those of skill in 
the art. For example, if the invented composition is calibrated at one 
dosage per day, the zinc levels in each dose may be adjusted such that a 
person taking multiple doses per day will ingest sufficient zinc to 
trigger an emetic response and cause expulsion of the overdose. 
E. Examples of Compositions 
The following examples will include embodiments within the scope of the 
invention, although the invention is not intended to be limited by or to 
these embodiments. These examples illustrate preferred modes of 
administering the invention as contemplated by the inventor. 
______________________________________ 
Example 1: 
androstenedione 100 mg 
green tea extract 50 mg 
(20% polyphenols) 
zinc (as arginate) 10 mg 
Example 2: 
androstenedione 100 mg 
green tea extract 50 mg 
(20% polyphenols) 
copper 0.5 mg 
zinc (as arginate) 10 mg 
Example 3: 
androstenedione 100 mg 
chrysin 50 mg 
zinc (as monomethionate) 
25 mg 
Example 4: 
androstenedione 50 mg 
Biochanin A 50 mg 
soy isoflavones (12%) 
200 mg 
Example 5: 
androstenedione 50 mg 
Red clover (Trifolium pratense) 
200 mg 
Saw Palmetto berry 60 mg 
standardized extract 
Example 6: 
DHEA 25 mg 
Green tea extract 50 mg 
(60% polyphenols) 
Pygeum africanum 100 mg 
Example 7: 
androstenedione 100 mg 
zinc (as amino acid chelate) 
15 mg 
Saw Palmetto berry 50 mg 
standardized extract 
Example 8: 
androstenedione 100 mg 
beta-sitosterol 200 mg 
zinc (as amino acid chelate) 
15 mg 
Example 9: 
androstenedione 100 mg 
tocotrienols (rice bran oil) 
150 mg 
zinc (as amino acid chelate) 
10 mg 
Example 10: 
androstenedione 100 mg 
Pygeum africanum 150 mg 
zinc (as amino acid chelate) 
10 mg 
Example 11: 
androstenedione 100 mg 
citrus bioflavonoids 500 mg 
isoflavone 100 mg 
Example 12: 
androstenedione 100 mg 
Genistein 20 mg 
Green tea extract 200 mg 
(80% polyphenols) 
Example 13: 
androstenedione 100 mg 
Alfalfa (Medicago satira) 
500 mg 
Green tea extract 200 mg 
(20% polyphenols) 
Example 14: 
androstenedione 100 mg 
Green tea extract 100 mg 
(80% polyphenols) 
Saw Palmetto berry extract 
60 mg 
zinc (as arginate) 10 mg 
Example 15: 
androstenedione 100 mg 
beta Sitosterol 100 mg 
Green tea extract 100 mg 
(80% polyphenols) 
Saw Palmetto berry extract 
60 mg 
Pygeum africanum 50 mg 
zinc (as arginate) 10 mg 
Example 16: 
androstenedione 100 mg 
soy saponin 50 mg 
Green tea extract (20%) 
100 mg 
Example 17: 
androstenedione 100 mg 
indole-3-carbinol 3 mg 
zinc (as arginate) 10 mg 
Example 18: 
DHEA 25 mg 
indole-3-carbinol 3 mg 
zinc (as arginate) 10 mg 
Example 19: 
androstenedione 100 mg 
Green tea extract (20%) 
100 mg 
zinc (as arginate) 10 mg 
calcium D-glucarate 500 mg 
Example 20: 
androstenedione 100 mg 
indole-3-carbinol 3 mg 
calcium D-glucarate 500 mg 
Example 21: 
androstenedione 50 mg 
chrysin 100 mg 
Hesperidin 100 mg 
Example 22: 
androstenedione 50 mg 
soy isoflavones 25 mg 
zearalenone 10 mg 
Example 23: 
Androstenedione 100 mg 
Red clover (Trifolium pratense) 
250 mg 
Green tea extract (20%) 
100 mg 
Example 24: 
androstenedione 100 mg 
alfalfa (coumesterol) 
250 mg 
zinc (monomethionate) 
25 mg 
Example 25: 
DHEA 25 mg 
androstenedione 50 mg 
chrysin 50 mg 
Green tea extract 200 mg 
(20% polyphenols) 
zinc (as arginate) 10 mg 
Example 26: 
androstenedione 100 mg 
Red clover 200 mg 
alfalfa 100 mg 
soy germ 200 mg 
citrus bioflavonoids 50 mg 
Green tea extract 200 mg 
(20% polyphenols) 
Example 27: 
androstenedione 100 mg 
formononetin 25 mg 
Saw palmetto berry extract 
60 mg 
Example 28: 
4-androstenediol 100 mg 
green tea extract 50 mg 
(20% polyphenols) 
copper (as lysinate) 0.5 mg 
zinc (as monomethionate) 
10 mg 
Example 29: 
5-androstenediol 100 mg 
green tea extract 50 mg 
(20% polyphenols) 
copper (as lysinate) 0.5 mg 
zinc (as monomethionate) 
10 mg 
Example 30: 
19-norandrostenedione 
100 mg 
Red Clover (Trifolium pratense) 
500 mg 
Pygeum africanum extract 
200 mg 
Example 31: 
pregnenolone 100 mg 
Ipriflavone 250 mg 
Pumpkin seed powder 200 mg 
Example 32: 
pregnenolone 100 mg 
19-norandrost-4-enediol 
50 mg 
Genistein (&gt;90%) 40 mg 
beta-Sitosterol 500 mg 
Example 33: 
pregnenolone 10 mg 
DHEA 25 mg 
androstenedione 50 mg 
4-androstenediol 25 mg 
19-norandrostenedione 
25 mg 
19-norandrost-4-enediol 
50 mg 
Green tea extract (90% polyphenols) 
200 mg 
Calcium D-glucarate 500 mg 
Zinc (as gluconate) 10 mg 
______________________________________ 
Suitable amounts of other natural products with anti-estrogen activity will 
include 
Alfalfa (Medicago sativa) (50-500 mg) 
Bee propolis (50-200 mg) 
7,8-Benzoflavones (10-50 mg) 
Biochanin A (10-50 mg) 
Broccoli extract (w/ sulforophane--50-500 mg) 
Calcium D-glucarate (200-500 mg) 
Chrysin (10-200 mg) 
Citrus bioflavonoids (50-2000 mg) 
Coumestrol (5-40 mg) 
Daidzein (&gt;90%-5-40 mg) 
Enterolactone (5-40 mg) 
Equol (5-40 mg) 
Flavone (&gt;90%-5-40 mg) 
Formononetin (&gt;90%-5-40 mg) 
Genistein (&gt;90%-5-40 mg) 
Glycetin (5-40 mg) 
Green tea extract 
(20% polyphenols--50-200 mg; 
40% polyphenols--40-100 mg; 
60% polyphenols--25-100 mg; 
80% polyphenols--20-100 mg; 
90% polyphenols--10-100 mg) 
Green tea powder (100-500 mg) 
Hesperidin (50-200 mg) 
Indole-3-carbinol (1-5 mg) 
Ipriflavone (50-250 mg) 
Naringer (50-100 mg) 
Naringenin (50-250 mg) 
Red Clover (Trifoliumpratense) (50-500 mg) 
Red palm oil (100-1000 mg) 
Rice bran oil (100-1000 mg) 
Orange juice solids (0.5-50 g) 
Phloretin (&gt;90%--5-40 mg) 
Quercetin (50-100 mg) 
beta-Sitosterol (50-200 mg) 
Soy isoflavones (2% in soy germ--100-500 mg; 12% in soy germ--50-200 mg) 
Soy saponin (50-250 mg) 
Tocotrienols (40%--100-500 mg) (e.g. rice bran oil) 
Tocotrienols (100-500 mg) (e.g. red palm oil) 
Tribulus terrestris (e.g., Tribestan.RTM.)) extracts (10-1000 mg) 
Zearalenol (5-40 mg) 
Zearalenone (5-40 mg) 
Zearalone (5-40 mg) 
Suitable amounts of other substances with anti-DHT activity will include: 
Calcium D-glucarate (500 mg) 
Green tea extract (20%--50-200 mg; 40%--40-150 mg; 60%--25-100 mg; 
80%--20-100 mg; 90%--10-100 mg) 
Green tea powder (100-500 mg) 
Pumpkin seed oil (100-500 mg) 
Pumpkin seed powder (100-500 mg) 
Pygeum africanum extract (50-200 mg) 
Pygeum africanum powder (100-500 mg) 
Saw palmetto berry extract (standardized to sterols--50-200 mg) 
Saw palmetto berry extract (standardized to fatty acids--50-200 mg) 
Saw palmetto berry powder (100-500 mg) 
beta-Sitosterol (50-500 mg) 
Tribulus terrestris (e.g., Tribestan.RTM.) extracts (10-1000 mg) 
Zinc salts (5-50 mg of elemental zinc) 
F. Human Experimental Data Using the Present Invention: 
An example of the present invention (see Exemplary Composition #2) was 
tested in a single adult human male, aged 41 years, who had an eight month 
history of resistance training, and was taking 25 mg of DHEA per day for 
15 months prior to start of the experiment. The subject was tested for 
baseline levels in serum of the following hormones: total testosterone, 
free testosterone, percentage (%) free testosterone, DHEA, DHEA-sulfate, 
androstenedione, 3-alpha-androstanediol glucuronide, and total estrogens 
Previous testing for total testosterone five months prior to baseline 
testing showed that DHEA supplementation at 25 mg per day for long time 
periods prior to the study period did not affect testosterone levels, 
indicating a steady state was reached for DHEA effects. The subject then 
took, as daily doses from an oral dietary supplement, 100 mg 
androstenedione, 50 mg green tea extract (20% polyphenols), 10 mg zinc (as 
arginate), and 0.5 mg copper (as lysinate). The subject also ingested 50 
mg of supplemental zinc (as gluconate) daily, which was a continuation of 
previous practices, and continued to take 25 mg of DHEA daily. The subject 
continued regular diet, supplementation, and exercise habits for 4.5 
months, after which another set of hormone levels was measured. 
The results are listed in the Table below. Initially, levels of each 
hormone measured were in the lower part of the reference ranges, 
consistent with the results of Alen, et al., 1988, indicating an 
overtraining syndrome. Free testosterone levels were below the reference 
range, in spite of consistent supplementation with DHEA. It can be seen 
that androstenedione supplementation was associated with increased levels 
of total testosterone, free testosterone, DHEA, DHEA-sulfate, 
androstenedione, 3-alpha-andtrostanediol glucuronide, and estrogens. 
Hormone levels, which prior to androstenedione supplementation were 
approaching deficient levels, were increased into safe levels at the 
middle or upper parts of reference ranges, i.e., a desired result. It can 
be seen that no hormone was elevated above the reference range, which 
would indicate a risk of side effects from testosterone and estrogen 
metabolites. Also desirable was the large percentage change for the chief 
androgen metabolite, 3-alpha-androstanediol glucuronide, indicating a 
healthy metabolic conversion of excess androgens to safe metabolites. 
The large increase in DHEA sulfate levels suggested that less DHEA was 
being used to provide androgenic hormones, and thus, DHEA sulfate levels 
rose to healthier levels. DHEA has important roles on its own for immune 
system modulation, brain function, and anticatabolic actions. In other 
words, androstenedione supplementation induced a DHEA-sparing action. In 
summary, the results showed safe increases of desired hormones, with no 
abnormally high levels of unwanted hormones, such as total estrogens. 
These results suggest that the exemplary composition of the present 
invention was successful in preventing unwanted side effects from 
long-term administration of androgenic testosterone precursors. 
In addition, the subject reported no side effects associated with 
androgenic or estrogenic actions. There was no reported or observable 
changes in acne, hirsutism, or prostate function. The subject did report 
an increase in body weight of 3 kg, along with large increases in 
strength, as exemplified by increases in pounds lifted in all 
weightlifting exercises. Thus, the claimed invention was associated with 
safe increases in androgenic hormone levels that most likely led to gains 
in muscle mass. 
TABLE 
______________________________________ 
Serum Hormone Levels Before and After Long-Term 
Supplementation with Androgenic Testosterone Precursors 
to Reduce Unwanted Side Effects 
Time Time % 
Hormone Reference Range 
0 4.5 months 
Change 
______________________________________ 
Testosterone, total 
241-830 ng/dl 
291 401 +37.8 
Testosterone, free 
13-40 pg/ml 12.3 14.7 +19.5 
% Free testosterone 
0.2-0.7% 0.42 0.37 -11.9 
Androstenedione 
50-250 ng/dl 
71 129 +45.0 
DHEA 1.4-12.5 ng/ml 
3.3 5.2 +57.6 
DHEA sulfate 
59-452 mcg/dl 
152 404 +166 
3-.alpha.-Androstanediol 
260-1500 ng/dl 
262 692 +164 
glucuronide 
Estrogens 40-115 pg/ml 
53 83 +56.6 
______________________________________ 
While the present invention has been described and illustrated in 
conjunction with a number of specific embodiments, those skilled in the 
art will appreciate that variations and modifications may be made without 
departing from the principles of the invention as herein illustrated, 
described and claimed. The invention may be embodied in other specific 
forms without departing from the spirit or essential characteristics 
thereof. The present embodiments are to be considered in all respects as 
illustrative, and not restrictive. The scope of the invention, is 
therefore, indicated by the appended claims rather than by the foregoing 
description, and all changes which come within the meaning and range of 
equivalency of the claims are to be embraced within their scope.