MALE HORMONE MODULATION THERAPY

If free testosterone levels are in the lower two thirds of the highest number in the reference range, but total testosterone is high-normal, and estradiol levels are not over 30, you should

Consider following some of the recommendations in the previous section to inhibit aromatase, since many of the same factors are involved in excess SHBG activity.
Take 320 mg a day of the super-critical extract of saw palmetto and 240 mg a day of the methanolic extract of nettle (Urtica dioica). Nettle may specifically inhibit SHGB (42-44, 251, 252), while saw palmetto may reduce the effects of excess estrogen by blocking the nuclear estrogen receptor sites in prostate cells, which in turn activate the cell-stimulating effects of testosterone and dihydrotestosterone. Saw palmetto also has the effect of blocking the oxidation of testosterone to androstenedione, a potent androgen that has been implicated in the development of prostate disease (253).

If total testosterone is in the lower one third of the reference range or below normal, and free testosterone is low, you should

See if your luteinizing hormone (LH) is below normal. If LH is low, your doctor can prescribe an individual dose of chorionic gonadotropin (HCG) hormone for injection. Chorionic gonadotropic hormone functions similarly to LH and can re-start testicular production of testosterone. Your doctor can instruct you about how to use tiny 30-gauge needles to give yourself injections two to three times a week.
After 1 month on chorionic gonadotropic hormone, a blood test can determine whether total testosterone levels are significantly increasing. You may also see your testicles growing larger. If total testosterone levels are restored, monitor blood levels of estradiol and free testosterone every 30 to 45 days for the first 5 months to be sure the exogenous testosterone you are using is following a healthy metabolic pathway, i.e., is raising your levels of free testosterone, but not increasing estradiol levels beyond 30.

If total testosterone remains low in spite of several months of chorionic gonadotropic hormone therapy, this indicates that your testicles are not capable of producing testosterone. In that case, initiate therapy with the testosterone patch, pellet, or cream. Do not use testosterone injections or tablets.

Before initiating testosterone replacement therapy, have a PSA blood test and a digital rectal exam to rule out detectable prostate cancer. Once total testosterone levels are restored to a high-normal range, monitor blood levels of estradiol, free testosterone, and PSA every 30 to 45 days for the first 6 months to make sure the exogenous testosterone you are using is following a healthy metabolic pathway and not causing a flare up of an underlying prostate cancer. The objective is to raise your levels of free testosterone to the upper third of the reference range, but to not increase estradiol levels beyond 30.

Excess estrogen (estradiol) blocks the production and effect of testosterone throughout the body, dampens sexuality, and increases the risk of prostate and cardiovascular disease. Once you have established the proper ratio of free testosterone (upper one third of the highest number in the reference range) and estradiol (not more than 30), make sure your blood is tested every 30 to 45 days for the first 5 months. Test every 6 months thereafter for free testosterone, estradiol, and PSA. For men in their 40s to 50s, correcting the excess level of estradiol is often all that has to be done. Men over 60 sometimes need the chorionic gonadotropin injection and may need to use a testosterone patch, cream, or pellet later in life (20).

Therapies

The Testosterone Patch and PSA

An oncologist affiliated with the Life Extension Foundation reports that some men on the testosterone patch will show an elevated PSA that then drops upon cessation of the exogenously administered testosterone. There are published studies that contradict this finding (185, 254-257). Elevation of PSA could be caused by the conversion of exogenous testosterone to estrogen or DHT.

Therapies have been discussed that can prevent testosterone from cascading into estrogen and DHT. This oncologist noted that prostate cancer patients with low testosterone levels have a more aggressive disease, most likely related to the development of tumor cells that are androgen independent and thus more resistant to therapy. This observation is substantiated by the published literature (185, 186, 201, 205, 224-229, 254-256, 286, 288).

"Andro" Supplements

Androstenedione is a precursor to both testosterone and estrogen. Early studies showed that "andro" supplements could markedly increase testosterone levels, but more recent studies cast doubt on this concept. A study in the Journal of the American Medical Association (1999) reported on an 8-week study showing that androstenedione supplements increased estrogen levels in 30 men (258). No increase in strength, muscle mass, or testosterone levels was observed. Meanwhile, home run-hitter Mark McGwire, who made androstenedione a media sensation, says he stopped taking the supplement in April 1999. Perhaps combining androstenedione with an aromatase inhibitor that would prevent it from converting to estrogen would make this precursor hormone work better in men. In the meantime, we suggest avoiding androstenedione until more definitive research is published.

Testosterone Drugs

Synthetic testosterone "steroid" drugs are chemically different from the testosterone your body makes and do not provide the same effect as natural testosterone. Some of the synthetic testosterone drugs to avoid using on a long-term basis are Methyltestosterone, Danazol, Oxandrolone, Testosterone propionate, cypionate, or enanthate.

The fact that testosterone is marketed as a "drug" does not mean it is not the same natural hormone your body produced. Scientists learned decades ago how to make the identical testosterone that your body produces, but since natural testosterone could not be patented, drug companies developed all kinds of synthetic testosterone analogs that could be patented and approved by the FDA as new drugs. Currently available recommended natural testosterone drugs are:

Androderm Transdermal System (SmithKline Beecham's testosterone patch)
Testoderm Transdermal System (Alza's testosterone patch)
Testosterone creams, pellets, and sublingual tablets (available from compounding pharmacies)

Both synthetic and natural testosterone drugs require a prescription, and a prescription should only be written after blood or saliva tests reveal a testosterone deficiency.

Alternative physicians usually prescribe testosterone creams and other types made at compounding pharmacies, whereas conventional doctors are more likely to prescribe a box of ready-made, FDA-approved testosterone patches. All forms of natural testosterone are the same and all will markedly increase free testosterone in the blood or saliva.

If you interact with children, you may want to avoid testosterone creams. There is a report of a young male child going through premature puberty after the child made contact with the testosterone cream on his father's body and on weightlifting equipment in the home. This unique case is a testament to the powerful effects that testosterone exerts in the body.

CAUTION: Do not use testosterone replacement if you have prostate cancer.

Men with existing prostate cancer should follow an opposite approach as it relates to testosterone. Prostate cancer patients are normally prescribed testosterone ablation therapy (using a drug that blocks the pituitary release of LH and another drug that blocks testosterone-receptor sites on the cells). Early-stage prostate cancer cells can often be controlled by totally suppressing testosterone in the body. Late-stage prostate cancer patients are sometimes put on drugs that produce estrogenic effects to suppress prostate cancer cells that no longer depend on testosterone for growth. Regrettably, prostate cancer patients on testosterone ablation therapy often temporarily have many of the unpleasant effects of low testosterone that have been described in this article. Before initiating a therapy that boosts your free testosterone level, a blood PSA (prostate specific antigen) test and digital rectal exam are recommended for men over age 40. While restoring free testosterone to healthy physiological levels (25-40 pg/mL) does not cause prostate cancer, it can induce existing prostate cancer cells to proliferate faster.

Natural Testosterone-Boosting/Estrogen-Suppressing Approaches

Chrysin

A bioflavonoid called chrysin has shown potential as a natural aromatase-inhibitor. Chrysin can be extracted from various plants. Body builders have used it as a testosterone boosting supplement since by inhibiting the aromatase enzyme, less testosterone is converted into estrogen. The problem with chrysin is that because of its poor absorption into the bloodstream, it has not produced the testosterone enhancing effects users expect. In a study published in Biochemical Pharmacology (1999), the specific mechanisms of chrysin's absorption impairment were identified, which infers that the addition of a pepper extract (piperine) could significantly enhance the bioavailability of chrysin (304). Pilot studies have found that when chrysin is combined with piperine, reductions in serum estrogen (estradiol) and increases in total and free testosterone result in 30 days. Aromatase-inhibiting drugs are used to treat Women with estrogen-dependant breast cancers. The rationale for this therapy is that estrogen is produced by fat cells via a process known as aromatization. Aging men often have excess aromatase enzyme activity, and the result is that too much of their testosterone is "aromatized" into estrogen.

In a study published in the Journal of Steroid Biochemical Molecular Biology (1993), chrysin and 10 other flavonoids were compared to an aromatase-inhibiting drug (aminoglutethimide) (298). The study tested the aromatase-inhibiting effects of these natural flavonoids (such as genistein, rutin, tea catechins, etc.) in human fat cell cultures. Chrysin was the most potent aromatase-inhibitor, and was shown to be similar in potency and effectiveness to the aromatase-inhibiting drug. The scientists conducting the study concluded by stating that the aromatase-inhibiting effects of certain flavonoids may contribute to the cancer preventive effects of plant-based diets (298). Two recent studies have identified specific mechanisms by which chrysin inhibits aromatase in human cells. These studies demonstrate that chrysin is a more potent inhibitor of the aromatase enzyme than phytoestrogens and other flavonoids that are known to have aromatase-inhibiting properties (299, 300). The purpose of these studies was to ascertain which fruits and vegetables should be included in the diet of postmenopausal Women to reduce the incidence of breast cancer. Excess levels of mutagenic forms of estrogen have been linked to a greater risk of breast cancer, and scientists are studying dietary means of naturally reducing levels of these dangerous estrogens. Flavonoids such as chrysin are of considerable interest because they suppress excess estrogen via their aromatase-inhibiting properties. While this cancer preventing effect is most important for Women, inhibiting aromatase in aging men has tremendous potential for naturally suppressing excess estrogen while boosting low levels of testosterone to a youthful state.

Since chrysin is not a patentable drug, do not expect to see a lot of human research documenting its effects. There are many FDA-approved drugs that inhibit aromatase (such as Arimidex), and there is not much economic interest in finding natural ways of replacing these drugs. While prescription aromatase-inhibiting drugs are relatively free of side effects, aging men who are seeking to gain control over their sex hormone levels sometimes prefer natural sources, rather than trying to convince a physician to prescribe a drug (such as Arimidex) that is not yet approved by the FDA as an anti-aging therapy. (Arimidex is prescribed to estrogen-dependant breast cancer patients to prevent testosterone and other hormones in the body from converting, i.e., aromatasing, into estrogen.)

An advantage to using plant extracts to boost testosterone in lieu of drugs is that the plant extracts have ancillary health benefits. Chrysin, for example, is a potent antioxidant that possesses vitamin-like effects in the body. It has been shown to induce an antiinflammatory effect, possibly through inhibition of the enzymes 5-lipoxygenase and cyclooxygenase inflammation pathways. Aging is being increasingly viewed as a proinflammatory process, and agents that inhibit chronic inflammation may protect against diseases as diverse as atherosclerosis, senility and aortic valve stenosis. Chrysin is one of many flavonoids being studied as a phyto-extract that may prevent some forms of cancer. If chrysin can boost free testosterone in the aging male by inhibiting the aromatase enzyme, this would provide men with a low cost natural supplement that could provide the dual anti-aging benefits of testosterone replacement and aromatase-inhibiting drug therapy. Pilot studies indicate that chrysin increases total and free testosterone levels in the majority of men who take it with piperine.

Chrysin has one other property that could add to its libido-enhancing potential. A major cause of sexual dissatisfaction among men is work-related stress and anxiety. Another problem some men have is "sexual performance anxiety" that prevents them from being able to achieve erections when they are expected to. In a study published in Pharmacology Biochemistry and Behavior (1994), mice were injected with diazepam (Valium), chrysin, or placebo to evaluate the effects these substances had on anxiety and performance levels. Chrysin was shown to produce anti-anxiety effects comparable with diazepam, but without sedation and muscle relaxation (301). In other words, chrysin produced a relaxing effect in the brain, but with no impairment of motor activity. The mechanism of action of chrysin was compared to diazepam, and it was shown that unlike diazepam, chrysin can reduce anxiety without inducing the common side-effects associated with benzodiazepine drugs.

A common problem with benzodiazepine drugs is memory impairment. In a study published in Pharmacology Biochemistry and Behavior (1997), chrysin displayed potent anti-anxiety effects in rats, but did not interfere with cognitive performance. In this study, diazepam was shown to inhibit neurological function, but chrysin (and other anti-anxiety flavonoids) had no effect on training or test session performance. The scientists conducting this study pointed out that chrysin selectively inhibits anxiety in the brain but, unlike diazepam, does not induce the cognitive impairment (302).

Chrysin may therefore offer libido-enhancing effects in the aging male by:

Increasing free testosterone
Decreasing excess estrogen
Producing a safe anti-anxiety effect.

Chrysin is being sold to body builders by commercial supplement companies that do not know if their product is favorably modulating testosterone and estrogen levels in men. The Life Extension Foundation, on the other hand, has conducted studies to evaluate the effects of chrysin (combined with piperine to facilitate absorption) on aging men.

Nettle

About 90% of testosterone is produced by the testes; the remainder is produced by the adrenal glands. Testosterone functions as an aphrodisiac hormone in brain cells and as an anabolic hormone in the development of bone and skeletal muscle. But testosterone that becomes bound to serum globulin is not available to cell receptor sites and fails to induce a libido effect. It is therefore desirable to increase levels of "free testosterone" in order to ignite sexual arousal in the brain.

As discussed already, a hormone that controls levels of free testosterone is called sex hormone-binding globulin (SHBG). When testosterone binds to SHBG, it loses its biological activity and becomes known as "bound testosterone," as opposed to the desirable "free testosterone." As men age past year 45, SHBG's binding capacity increases almost dramatically?by 40% on average?and coincides with the age-associated loss of libido.

Some studies show that the decline in sexual interest with advancing age is not always due to the amount of testosterone produced, but rather to the increased binding of testosterone to globulin by SHBG. This explains why some older men who are on testosterone replacement therapy do not report a long-term aphrodisiac effect. That is, the artificially administered testosterone becomes bound by SHBG and is not bioavailable to cellular receptor sites where it would normally produce a libido-enhancing effect.

It should be noted that the liver also causes testosterone to bind to globulin. This liver-induced binding of testosterone is worsened by the use of sedatives, anti-hypertensives, tranquilizers, and alcoholic beverages. The overuse of drugs and alcohol could explain why some men do not experience a libido-enhancing effect when consuming drugs and plant-based aphrodisiacs. An interesting review entitled "How Desire Dies" (Nature, 381/6584, 1996) discusses how frequently prescribed drugs, such as beta-blockers and antidepressants, cause sexual dysfunction. Prescription drugs of all types have been linked to inhibition of libido.

Logically, one way of increasing libido in older men would be to block the testosterone-binding effects of SHBG. This would leave more testosterone in its free, sexually activating form.

A highly concentrated extract from the nettle root provides a unique mechanism for increasing levels of free testosterone. Recent European research has identified constituents of nettle root that bind to SHBG in place of testosterone, thus reducing SHBG's binding of free testosterone (309-313). As the authors of one study stated, these constituents of nettle root "may influence the blood level of free, i.e., active, steroid hormones by displacing them from the SHBG binding site."

The prostate gland also benefits from nettle root. In Germany, nettle root has been used as a treatment for benign prostatic hyperplasia (enlargement of the prostate gland) for decades. A metabolite of testosterone called dihydrotestosterone (DHT) stimulates prostate growth, leading to enlargement. Nettle root inhibits the binding of DHT to attachment sites on the prostate membrane.

Nettle extracts also inhibit enzymes such as 5 alpha reductase that cause testosterone to convert to DHT. It is the DHT metabolite of testosterone that is known to cause benign prostate enlargement, excess facial hair, and hair loss at the top of the head.

Muira puama

French scientists have identified an herbal extract that has shown libido-enhancing effects in two human clinical studies. Muira puama comes from the stems and roots of the Ptychopetalum olacoides plant and is widely used in the Amazon region of South America as an aphrodisiac, tonic, and cure for rheumatism and muscle paralysis.

Muira puama has been the subject of two published clinical studies conducted by Dr. Jacques Waynberg, an eminent medical sexologist and author of ten books on the subject. The first study, conducted at the Institute of Sexology in Paris under Waynberg's supervision, was reported in the November 1994 issue of The American Journal of Natural Medicine. The study population consisted of 262 men complaining of lack of sexual desire or inability to attain or maintain erection. After 2 weeks, 62% of patients with loss of libido rated the treatment as having a dynamic effect, while 52% of patients with erectile dysfunction rated the treatment as beneficial. The article goes on to compare muira puama favorably to Yohimbeine, stating, "Muira puama may provide better results than Yohimbeine without side effects."

Dr. Waynberg's second study, entitled "Male Sexual Asthenia," focused on sexual difficulties associated with asthenia, a deficiency state characterized by fatigue, loss of strength, or debility, all symptoms of a testosterone deficiency. The study population consisted of 100 men over 18 years of age who complained of impotence or loss of libido or both. A total of 94 men completed the study and were evaluated. Muira puama treatment led to significantly increased frequency of intercourse for 66% of couples. Of the 46 men who complained of loss of desire, 70% reported intensification of libido. The stability of erection during intercourse was restored in 55% of patients and 66% of men reported a reduction in fatigue. Other beneficial effects included improvement in sleep and morning erections.

Treatment with muira puama was much more effective in cases with the least psychosomatic involvement. Of the 26 men diagnosed with common sexual asthenia without noticeable sign of psychosomatic disorder, the treatment was effective for asthenia in 100% of cases, the lack of libido in 85% of cases, and for inability of coital erection in 90% of cases.

The latter finding confirms that broad tonic action of muira puama on conditions of fatigue and stress-related sexual dysfunction. Since muira puama is not an artificial stimulant, it fortifies the system over a period of time. Some men report increased vitality within 2 weeks, while the full effects build over several weeks.

Dr. Waynberg notes that his toxicology studies and observations corroborate the conclusions of the scientific literature on the absence of toxicity of muira puama, which is well tolerated by men in general good health.

One of the earliest scientific studies of muira puama was conducted by another French doctor, Dr. Rebourgeon. His research found the plant to be effective in "gastrointestinal and circulatory asthenia as well as impotence." Three of the most respected scientific authorities on medical herbalism recommend muira puama. In published books, James Duke, Ph.D., Chief of the United States Department of Agriculture's Medical Plant Laboratory (314), and Michael Murray, M.D. (315) recommend muira puama for erectile dysfunction or lack of libido. In addition, Daniel Mowrey, Ph.D., in Herbal Tonic Therapies (316), stated:

"Based on the clinical reports documenting the libido and energy enhancing effects of muira puama, it is possible that this herb induces these positive changes by favorably altering the hormone balance in aging men, i.e., increases free testosterone and/or suppresses excess estrogen."

Human Hormone Modulation Studies Using Nutrients

In order to ascertain the safety and efficacy of nutrients that are purported to modulate male hormone levels, The Life Extension Foundation sponsored clinical studies to assess the effects of specific supplements on blood levels of testosterone, estrogen, SHBG, etc. (307). The nutrients tested included various combinations of chrysin, nettle root, maca, ginger root, muira puama, and zinc along with piperine to enhance the absorption of the chrysin.

The results from the first pilot study showed that nine out of ten men experienced a significant reduction in serum estradiol (estrogen) levels after only 30 days, compared to baseline. In this brief study, total testosterone increased in seven out of ten men, but free testosterone increased in only four of the ten men studied. Other blood parameters were not statistically altered.

A more comprehensive study incorporating a different combination of nutrients resulted in eight out of eight men experiencing increases in free testosterone while levels of the undesirable SHBG declined in seven out of eight men, compared to baseline. Estrogen and other blood parameters were not significantly altered in this study.

A third study was undertaken to evaluate still another combination of nutrients. It revealed that after 30 days, 12 out of 17 men experienced an increase in total testosterone and 11 out of 17 showed an increase in free testosterone, compared to baseline. Again, other blood parameters were not significantly altered.

Based on the results of these studies, a formula called Super MiraForte was developed that contains the combination of chrysin, nettle root, muira puama, piperine, and other nutrients that showed the most potent effects in boosting free testosterone and suppressing estrogen in aging men. For those who would prefer to avoid testosterone boosting and estrogen suppressing drugs, four capsules a day of Super MiraForte may be considered.

Mandatory Testing

When embarking on a hormone modulation program, medical testing is critical. First, a baseline blood PSA must be taken to rule out existing prostate cancer. Then free testosterone and estradiol tests are needed to make sure that too much testosterone is not being converted into estradiol (estrogen). If estrogen levels are too high, the use of aromatase inhibitors can keep testosterone from converting (aromatizing) into estrogen in the body. Follow-up testing for testosterone, estrogen, and PSA are needed to rule out occult prostate cancer and to fine tune your program. It is possible that testosterone patches and creams can increase testosterone levels too much. In that case, blood or saliva testing could save you money by allowing you to use less of the testosterone drug.

There are now natural dietary supplements in development that boost free testosterone levels and suppress excess estrogen. Even when these supplements become available, PSA testing is still mandatory, since any substance that increases testosterone should be avoided by most prostate cancer patients.

Testosterone Caveats

Please, after reading all of this, do not just "treat a number." In dealing with sexual function and libido, there is always a large psychological component to enhancing or regaining performance. There are also many physical causes of dysfunction. Do not assume that a certain test number means guaranteed results or you may end up with performance anxiety over that. If you have genuine symptoms, definitely try this protocol, it is well thought out and proven. But remember to include all the other stressors and factors in your lifestyle into the equation.

More Information

The best source for actual case histories of men who successfully used hormone modulation is Dr. Eugene Shippen's book entitled The Testosterone Syndrome (260). Dr. Shippen provides many interesting details too numerous to be covered in this concise protocol. Another book, Maximize Your Vitality & Potency, by Dr. Jonathan Wright also contains historical and more technical data about the benefits of testosterone that are, again, too numerous to include in this protocol (305). Note: These two books are available from the Life Extension Foundation.

Studies

Because of the highly controversial nature of this article, Life Extension has taken the unprecedented step of publishing over 180 pages of scientific abstracts on our web site that are numerically matched to the statements made in this article. This may be the first time for such a massive undertaking, and it reflects the urgent need to convey this information to skeptical physicians so that they will prescribe testosterone and aromatase-inhibiting drugs to individuals whose blood tests indicate a need for these therapies.

What the Published Literature Says about Testosterone and Prostate Cancer

Studies indicating that testosterone does not cause prostate cancer.

Study 1. "This nested case-control study was based on the cohort of men who donated blood to the Janus serum bank at Oslo University Hospital between 1973 and 1994. Cancer incidence was ascertained through linkage with the Norwegian Cancer Registry. The study included sera from 59 men who developed prostate cancer subsequent to blood donation and 180 men who were free of any diagnosed cancer in 1994 and were of similar age and had similar blood storage time. Neither testosterone, DHT, nor the ratio of testosterone to DHT was associated with risk of developing prostate cancer. These results showed no association, positive or negative, between androgens measured in serum and the subsequent risk of developing prostate cancer)" (212). (Vatten et al. Cancer Epidemiology Biomarkers Prev. 1997 Nov; 6(11): 967-9. Study conducted at Department of Community Medicine and General Practice, University Medical Center, Trondheim, Norway [lars.vatten@medisin.ntnu.no].)

Study 2. "We conducted a nested case-control study in a cohort of 6860 Japanese-American men examined from 1971 to 1975. At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 141 tissue-confirmed incident cases of prostate cancer were identified, and their stored sera and those of 141 matched controls were assayed for total testosterone, free testosterone, dihydrotestosterone, 3-alpha-androstanediol glucuronide, androsterone glucuronide, and androstenedione. The findings of this study indicate that none of these androgens is strongly associated with prostate cancer risk" (213). (Nomura et al. Cancer Epidemiol. Biomarkers Prev. 1996 Aug; 5(8): 621-5. Study conducted at Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu, HI 96817.)

Study 3. "Prostate cancer was identified in 14% (11/77) of the entire group and in 10 men (29%) aged 60 years or older. The median age for men with cancer was 64 years. No significant differences were noted between the cancer and benign groups with regard to PSA level, PSA density, prostate volume, total testosterone level, or free testosterone level. A high prevalence of biopsy-detectable prostate cancer was identified in men with low total or free testosterone levels despite normal PSA levels and results of digital rectal examination. These data suggest that (1) digital rectal examination and PSA levels are insensitive indicators of prostate cancer in men with low total or free testosterone levels, and (2) PSA levels may be altered by naturally occurring reductions in serum androgen levels" (206). (Morgentaler et al. J. Am. Med. Assoc. 1996 Dec 18; 276(23): 1904-6. Study conducted at Division of Urology, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215.)

Study 4. "We conducted a prospective nested case-control study to evaluate the relationships of serum androgens and estrogens to prostate cancer using serum collected at baseline for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. None of the individual androgens or estrogens was significantly related to prostate cancer. These results do not support a strong relationship of serum androgens and estrogens with prostate cancer in smokers" (189). (Dorgan et al. Cancer Epidemiol. Biomarkers Prev. 1998 Dec; 7(12): 1069-74. Study conducted at Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-7374 [jd7g@nih.gov].)

Study 5. "We report a nested case-control study of serum biomarkers of 5-alpha-reductase activity and the incidence of prostate cancer. From a cohort of more than 125,000 members of the Kaiser Permanente Medical Care Program who underwent multiphasic health examinations during 1964-1971, we selected 106 incident prostate cancer cases. A control was pair matched to each case on age, date of serum sampling, and clinic location. The adjusted odds ratios and 95% confidence intervals for a one quartile score increase were 1.00 for total testosterone (1.00 = no increased risk), 1.14 for free testosterone, 1.13 for androsterone glucuronide, and 1.16 for 3-alpha-diol G" (190). (Guess et al. Cancer Epidemiology Biomarkers Prev. 1997 Jan; 6(1): 21-4. Study conducted at Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7400.)

Study 6. "Serum samples were obtained from 6860 men during their study examination from 1971 to 1975. After a surveillance period of about 14 years, 98 incident cases of prostate cancer were identified. Their stored sera and that of 98 matched controls from the study population were tested for the following: testosterone, dihydrotestosterone, estrone, estradiol, and sex hormone globulin. There was a suggestion that serum dihydrotestosterone levels were lower and the testosterone/dihydrotestosterone ratios were higher in the prostate cancer cases compared with their controls. However, none of these associations or that of the other hormones was strongly significant" (191). (Nomura et al. Cancer Res. 1988 Jun 15; 48(12): 3515-7. Study conducted at Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu, HI 96817.)

Study 7. "A case-control study of prostatic cancer was carried out to examine the association between selected physical characteristics and factors related to sexual development and behavior and the risk for this disease. The levels of testosterone (T), dihydrotestosterone, salivary testosterone and T/SHBG (sex hormone-binding globulin) did not vary with age. Older men had higher oestradiol (estrogen) levels. Further, little association between hormone levels and risk factors was found, except for married subjects having increased serum androgens and heavy subjects having decreased serum androgens (not significant)" (192). (Hayes et al. Eur. J. Cancer Prev. 1992 Apr; 1(3): 239-45. Study conducted at Department of Urology, Erasmus University, Rotterdam, The Netherlands.)

Study 8. "A population-based nested case-control study was conducted to determine the relation of prediagnostic serum levels of testosterone, dihydrotestosterone, prolactin, follicle-stimulating hormone, luteinizing hormone, estrone, and estradiol to the risk of subsequent prostate cancer. Serum speciMens of study subjects were available from a blood collection campaign in Washington County, Maryland, in 1974. There were no significant differences in levels of these hormones between cases and controls, although elevated levels of luteinizing hormone and of testosterone/dihydrotestosterone ratios were associated with mild increased risks of prostate cancer" (194). (Hsing et al. Cancer Epidemiol. Biomarkers Prev. 1993 Jan-Feb; 2(1): 27-32. Study conducted at National Cancer Institute, Division of Cancer Etiology, Bethesda, MD 20892.)

Study 9. "The possible relationship between changes in peripheral hormone levels and the occurrence of prostatic pathology was studied in a case-control study involving estimation of various plasma hormones in 368 Dutch and 258 Japanese men, who were grouped as controls and patients with benign prostatic hyperplasia, focal prostatic carcinoma, or clinically evident prostatic carcinoma. There were no significant differences in plasma androgen levels between Japanese or Dutch prostate cancer cases and their respective control subgroups. These findings do not support a correlation between the lower plasma testosterone levels and a lower incidence of prostate cancer in the Japanese men. Furthermore, no significant differences were found between salivary levels of testosterone or the ratio between testosterone and SHBG in the various Dutch subgroups. In Japanese benign prostatic hyperplasia patients, the testosterone to SHBG ratio was significantly increased. In conclusion, the results of this retrospective, cross-sectional study do not indicate that hormonal levels play a primary role in the origin or promotion of prostatic abnormalities" (195). (de Jong et al. Cancer Res. 1991 Jul 1; 51(13): 3445-50. Study conducted at Department of Endocrinology and Reproduction, Erasmus University, Rotterdam, The Netherlands.)

Study 10. "Frozen serum samples were analysed for PSA, DHT, testosterone and SHBG, and compared to the diagnosis and tumor stage, grade and ploidy. DHT levels were slightly lower in patients with prostate cancer but the difference was not statistically significant. There was a trend towards lower DHT values in more advanced tumors. Testosterone levels were lower in patients with cancer than in the control group, but the differences were not significant. There was no correlation between testosterone levels, tumor stage, and ploidy. The testosterone/DHT ratio tended to be higher in patients with more advanced tumors. SHBG levels were lower in patients with cancer than in controls, but the differences were not statistically significant. There were no systematic variations of tumor stage, grade, and ploidy. Within a group, DHT levels tended to be lower among cases and in those with more advanced tumors. No systematic variation was found in the levels of testosterone or SHBG" (197). (Gustafsson et al. Br. J. Urol. 1996 Mar; 77(3): 433-40. Study conducted at Department of Urology, Karolinska Institute at Stockholm Soder Hospital, Sweden.)

Study 11. "Index cases and their brothers and sons had a significantly lower mean plasma testosterone content than controls of comparable age. Preliminary data suggest that the metabolic clearance rate of testosterone and the conversion ratio of testosterone to estradiol are relatively high in probands. The observations indicate that familial factors are potent risk factors for the development of prostatic cancer. They also suggest that plasma androgen values in families with prostatic cancer cluster in the lower range of normal and that plasma sex-steroid content is more similar in each brother with or without prostatic cancer than among non-brothers" (198). (Meikle et al. Prostate 1985; 6(2): 121-8.)

Study 12. "Baseline sex hormone levels were measured in 1008 men ages 40 to 79 years who had been followed for 14 years. There were 31 incident cases of prostatic cancer and 26 identified from death certificates with unknown dates of diagnosis. In this study, total testosterone, estrone, estradiol, and sex hormone-binding globulin were not related to prostate cancer, but plasma androstenedione showed a positive dose-response gradient" (199). (Barrett-Connor et al. Cancer Res. 1990 Jan 1; 50(1): 169-73. Study conducted at Department of Community and Family Medicine, University of California, San Diego, La Jolla, CA 92093.)

Study 13. "The hypothesis that serum concentrations of pituitary hormones, sex steroid hormones, or sex hormone-binding globulin (SHBG) affect the occurrence of prostatic cancer was tested in a consecutive sample of 93 patients with newly diagnosed, untreated cancer and in 98 population controls of similar ages without the disease. Remarkably close agreement was found for mean values of total testosterone (15.8 in cases and 16.0 in controls), and free testosterone (0.295 and 0.293, respectively), with corresponding odds ratios for the highest vs. lowest tertile of 1.0 (1.00 = no increased risk) for testosterone and 1.2 for free testosterone. Similar close agreement between cases and controls was found for serum concentrations of estradiol, androstenedione, and SHBG, although the mean estradiol level was nonsignificantly lower among cases" (200). (Andersson et al. Br. J. Cancer 1993 Jul; 68(1): 97-102. Study conducted at Department of Urology, Orebro Medical Center Hospital, Sweden.)

Study 14. "Modest depression of serum testosterone and estradiol was noted for prostate cancer patients compared to clinic controls, although the differences were not statistically significant. This depression was interpreted to be a likely result of the malignant process rather than a cause of it" (202). (Hulka et al. Prostate 1987; 11(2): 171-82. Study conducted at Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, NC 27514.)

Study 15. "The prostate cancer patients had a slightly lower mean free testosterone and mean estradiol/free T ratio than the prostate enlargement patients. The mean estradiol/free testosterone ratio was significantly higher in the prostate enlargement patients and in the PC patients than in the young controls. It seems possible that the observed age-dependent significant increase in plasma estrogen concentration in the prostate enlargement patients may act as a protective factor against prostatic cancer" (203). (Rannikko et al. Prostate 1983; 4(3): 223-9.)

Study 16. "A fourfold higher relative risk for the development of prostatic cancer was observed for brothers of prostatic cancer cases compared to their brothers-in-law and males in the general population of the state of Utah. Probands and their brothers, and sons of the patients with the disease, had significantly lower plasma testosterone levels than controls of comparable age. This is the first documentation indicating that familial (possibly genetic) factors are potent risk factors for predisposing men to the development of prostatic cancer and in regulating the plasma content of androgens. Our results indicate that plasma androgen levels in families with prostatic cancer are clustered in the lower range of the normal population. They also suggest that plasma androgen content is more similar within each family with the cancer than among the families without cancer" (204). (Meikle et al. J. Clin. Endocrinol. Metabol. 1982 Jun; 54(6): 1104-8.)

Study 17. "Pretreatment hormone levels were determined in 222 patients with prostatic cancer and their prognostic value assessed. The patients were grouped into yearly survival categories and only those whose cause of death was due to the disease were included in the study. Low concentrations of testosterone in plasma at the time of diagnosis related to a poor prognosis. Patients who died within 1 year of diagnosis had the lowest mean plasma levels of this steroid. The pretreatment mean plasma testosterone concentrations were found to be higher as the survival period of the various groups lengthened. The indications from this study are that poor testicular function is associated with early death from prostatic carcinoma and that the measurement of blood levels of testosterone at diagnosis could provide a prognosis of subsequent life span" (205). (Harper et al. Eur. J. Cancer Clin. Oncol. 1984 Apr; 20(4): 477-82.)

Study 18. "Pretreatment plasma concentrations of total testosterone, prolactin, and total estradiol were measured in 123 prostatic cancer patients who were categorized into groups according to the UICC classification. The mean follow-up time was 48 months. Higher pretreatment estradiol and testosterone levels were associated with better survival" (207). (Haapiainen et al. Scand. J. Urol. Nephrol. Suppl. 1988; 110: 137-43. Study conducted at Second Department of Surgery, Helsinki University Central Hospital, Finland.)

Study 19. "This cross-sectional study was undertaken to determine whether serum hormones (free testosterone, androstenedione, luteinizing hormone, or prolactin) have any influence on serum prostate specific antigen (PSA) levels in patients with stage A-C prostate cancer. None of the hormones in any of the analyses showed any association to serum PSA values. Serum free testosterone, androstenedione, and luteinizing hormone appeared to have no influence on serum PSA values in nonmetastatic cancer patients" (208). (Vijayakumar et al. J. Natl. Med. Assoc. 1995 Nov; 87(11): 813-9. Study conducted at Department of Radiation Oncology, Michael Reese Hospital, Center for Radiation Therapy, University of Chicago, IL.)

Study 20. "Serum levels of testosterone, DHT, androsterone, 5 alpha-androstane-3 alpha, 17- beta-diol (5 alpha-diol), and estradiol were measured by radioimmunoassay in the sera of 9 patients with untreated prostatic cancer and in 11 with benign prostatic hypertrophy (prostate enlargement). Although no specific changes in steroid hormone levels in either disease group were found, response patterns of serum T, DHT, and E2 were shown to be those characteristic of male senescence, suggesting a relative predominance of estrogens over androgens" (211). (Isurugi et al. Prostate Suppl. 1981; 1: 19-26.)

Study 21. "We studied the effect of exogenous testosterone administration on the serum levels of PSA (prostate-specific antigen) and PSMA (prostate-specific membrane antigen) in hypogonadal men. Serial serum PSA, serum PSMA, and serum total testosterone levels were obtained at intervals of every 2 to 4 weeks in 10 hypogonadal men undergoing treatment with exogenous testosterone, delivered as testosterone enanthate injection or by testosterone patch. A two-tailed, paired t-test failed to demonstrate a significant correlation between serum PSA or PSMA and serum testosterone levels. This study suggests that in hypogonadal men, neither PSMA nor PSA expression is testosterone-dependent" (185). (Douglas et al. J. Surg. Oncol. 1995 Aug; 59(4): 246-50. Study conducted at Department of Surgery, Walter Reed Army Medical Center, Washington, D.C. 20307-5001.)

Neutral study

Study 22. "Blood samples were collected from 52 incident cases of histologically confirmed prostate cancer and 52 age- and town of residence-matched healthy controls in Athens, Greece. DHT was associated inversely, significantly, and strongly with the risk of prostate cancer, whereas testosterone was associated marginally positively, and E2 was associated non-significantly inversely with the disease" (193). (Signorello et al. Cancer Causes Control 1997 Jul; 8(4): 632-6. Study conducted at Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, MA 02115.)

Studies indicating that testosterone causes prostate cancer

Study 1. "We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer. No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P <.001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk. High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor" (214). (Gann et al. J. Natl. Cancer Inst. 1996 Aug 21; 88(6): 1118-26. Study conducted at Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA.)

Study 2. "Basal serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), and gonadotrophins, and the basal levels and response to adrenocorticotropic hormone (ACTH) of adrenocortical steroids, were measured before treatment in 72 patients with prostate cancer and in 42 age-matched healthy controls. Patients aged <60 years with prostate cancer had significantly elevated levels of total testosterone and unconjugated (E1) and total (tE1) oestrone, while patients aged > or = 60 years had significantly elevated levels of total and non-SHBG-bound testosterone (NST), 17-alpha-hydroxyprogesterone and tE1. Gonadotrophins, SHBG levels and relationships between total testosterone and SHBG were normal in both age groups of patients, as were basal levels and ACTH-induced increments of adrenocortical steroids. The patients had normal age-related variations in SHBG and NST and in basal levels and ACTH-induced increments of adrenocortical steroids. There was a significant age-related increase in serum E1 in the control subjects but not in the patients. Patients with metastatic disease had significantly lower E1 levels than had patients without metastases. The results suggest an increased sensitivity of the testis to gonadotrophic stimulation, as well as an increased peripheral oestrogen synthesis in patients with prostate cancer, the latter being most pronounced in younger subjects. Men developing prostate cancer may have been exposed to a combination of elevated endogenous oestrogen and androgen levels for a long time. These findings support the theory of a synergism between oestrogens and androgens as an important factor in the aetiology of prostate cancer" (196). (Carlstrom et al. Br. J. Urol. 1997 Mar; 79(3): 427-31. Study conducted at Department of Obstetrics and Gynaecology, Karolinska Institute, Huddinge University Hospital, Sweden.)

Study 3. "A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cases/156 controls). Free testosterone was greater among cases than in controls (16.4 +/-6.1 vs. 14.9 +/-4.8 pg/ml, P = 0.02). Conversely, DHT- related ratios were greater among controls. Data suggest that increased levels of free testosterone may be a risk factor for prostatic carcinoma" (216). (Demark-Wahnefried et al. J. Androl. 1997 Sep-Oct; 18(5): 495-500. Study conducted at Division of Urology, Duke University Medical Center, Durham, NC 27710.)

Study 4. "We present the case of a hypogonadal patient in whom a 20-fold increase in prostate-specific antigen and a palpable prostatic nodule developed 6 months into the administration of intramuscular testosterone" (217). (Curran et al. Urology 1999 Feb; 53(2): 423-4. Study conducted at Department of Urology, Lahey Clinic Medical Center, Burlington, MA 01805.)

Study 5. "The metabolic clearance and production rates of testosterone were significantly higher in (prostate cancer) patients than in controls. These results indicate that men with prostatic cancer have elevated clearance and production rates of testosterone without an alteration of estradiol production or clearance" (215). (Meikle et al. J. Steroid Biochem. 1989 Jul; 33(1): 19-24. Study conducted at Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132.)

Summary

Before beginning testosterone replacement, comprehensive blood testing is necessary to determine liver-kidney function, and levels of glucose, minerals, lipids, thyroid, free and total testosterone, estadiol, DHT, DHEA, PSA, homocysteine, LH (optional), and SHBG (optional). A digital rectal exam is also recommended to eliminate the possibility of prostate cancer. The Life Extension Foundation highly recommends natural testosterone over synthetic types that have a different chemical structure than the testosterone produced in the body. Nutritional supplements may be added to the diet depending upon test results that can enhance libido and prevent testosterone from cascading into estrogen and DHT.

Soy isoflavones contained in Mega Soy Extract will help remove excess estrogen from the blood, 2 capsules daily.
Zinc functions as an aromatase inhibitor in some men, 80-90 mg daily.
Super MiraForte containing chrysin, piperine, nettle, and muira pauma boosts free testosterone and acts as a mild aromatase inhibitor, 2 capsules daily.
Natural Prostate Formula containing nettle and saw palmetto helps to inhibit SHGB and reduce the effects of excess estrogen, 2 capsules daily.
The herbal extract muira puama has shown libido enhancing effects and may increase levels of free testosterone, while suppressing excess estrogen, 500 mg daily.

Product availability: Mega Soy Extract, OptiZinc, Super MiraForte, and Natural Prostate Formula are available by calling (800)544-4440 or order online. Testosterone patches, creams, gels, Proscar and Arimidex are prescription drugs.

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These statements have not been evaluated by the FDA. These products are not intended to diagnose, treat, cure, or prevent any disease