THE TESTOSTERONE DOCTOR Eugene Shippen, M.D. (co-author of The Testosterone Syndrome, 1998) provided extensive evidence documenting the pathology of the testosterone deficiency syndrome in men. Some excerpts follow from a lecture presented by Dr. Shippen at the American Academy for Anti-Aging Medicine Conference in December 1998: First, testosterone is not just a "sex hormone." It should be seen as a "total body hormone," affecting every cell in the body. The changes seen in aging, such as the loss of lean body mass, the decline in energy, strength, and stamina, unexplained depression, and decrease in sexual sensation and performance, are all directly related to testosterone deficiency. Degenerative diseases such as heart disease, stroke, diabetes, arthritis, osteoporosis, and hypertension are all directly or indirectly linked to testosterone decline (220-223). Secondly, testosterone also functions as a pro-hormone. Local tissue conversion to estrogens, dihydrotestosterone (DHT), or other active metabolites plays an important part in cellular physiology. Excess estrogen seems to be the culprit in prostate enlargement. Low testosterone levels are in fact associated with more aggressive prostate cancer (201, 205, 224-229). While fear of prostate cancer keeps many men from testosterone replacement, it is in fact testosterone deficiency that leads to the pathology that favors the development of prostate cancer. Testosterone improves cellular bioenergetics. It acts as a cellular energizer. Since testosterone increases the metabolic rate and aerobic metabolism, it also dramatically improves glucose metabolism and lowers insulin resistance (76, 80, 230). Another myth is that testosterone is bad for the heart. Actually, low testosterone correlates with heart disease more reliably than does high cholesterol (19, 231). Testosterone is the most powerful cardiovascular protector for men. Testosterone strengthens the heart muscle (232); there are more testosterone receptors in the heart than in any other muscle. Testosterone lowers LDL cholesterol and total cholesterol (69, 81, 111) and improves every cardiac risk factor. It has been shown to improve or eliminate arrhythmia and angina (9, 106, 113-115, 233, 266). Testosterone replacement is the most underutilized important treatment for heart disease. Testosterone shines as a blood thinner, preventing blood clots (32). Testosterone also helps prevent colon cancer (235, 236). Previous research on testosterone used the wrong form of replacement. Injections result in initial excess of testosterone, with conversion of excess to estrogens. Likewise, total testosterone is often measured instead of free testosterone, the bioavailable form. Some studies do not last long enough to show improvement. For instance, it may take six months to a year before the genital tissue fully recovers from atrophy caused by testosterone deficiency, and potency is restored. Physicians urgently need to be educated about the benefits of testosterone and the delicate balance between androgens (testosterone) and estrogens. Each individual has his or her own pattern of hormone balance; this indicates that hormone replacement should be individualized and carefully monitored. OBESITY AND HORMONE IMBALANCE A consistent finding in the scientific literature is that obese men have low testosterone and very high estrogen levels. Central or visceral obesity ("pot belly") is recognized as a risk factor for cardiovascular disease and Type-II diabetes. Research has shed light on subtle hormone imbalances of borderline character in obese men that often fall within the normal laboratory reference range. Boosting tes-tosterone levels seems to decrease the abdominal fat mass, reverse glucose intolerance, and reduce lipoprotein abnormalities in the serum. Further analysis has also disclosed a regulatory role for testosterone in counteracting visceral fat accumulation. Epidemiological data demonstrate that relatively low tes-tosterone levels are a risk factor for development of visceral obesity (7, 237). One study showed that serum estrone and estradiol were elevated twofold in one group of morbidly obese men. Fat cells synthesize the aromatase enzyme, causing male hormones to convert to estrogens (278). Fat tissues, especially in the abdomen, have been shown to literally "aromatize" testosterone and its precursor hormones into potent estrogens (80, 237-242). Eating high-fat foods may reduce free testosterone levels according to one study that measured serum levels of sex steroid hormones after ingestion of different types of food. High-protein and high-carbohydrate meals had no effect on serum hormone levels, but a fat-containing meal reduced free testosterone levels for 4 hours (243). Obese men have testosterone deficiency caused by the production of excess aromatase enzyme in fat cells and also from the fat they consume in their diet. The resulting hormone imbalance (too much estrogen and not enough free testosterone) in obese men partially explains why so many are impotent and have a wide range of premature degenerative diseases (45). FACTORS CAUSING THE ESTROGEN- TESTOSTERONE IMBALANCE IN MEN Excess "Aromatase" Enzyme Liver Enzymatic Activity Obesity Zinc Deficiency Lifestyle Changes If your blood tests reveal high estrogen and low tes-tosterone, here are the common factors involved: Excess "Aromatase" Enzyme As men age, they produce larger quantities of an enzyme called aromatase. The aromatase enzyme converts testosterone into estrogen in the body (17, 240, 241, 244, 245). Inhibiting the aromatase enzyme results in a significant decline in estrogen levels while often boosting free testosterone to youthful levels. Therefore, an agent designated as an "aromatase inhibitor" may be of special value to aging men who have excess estrogen. Liver Enzymatic Activity A healthy liver eliminates surplus estrogen and sex hormone-binding globulin. Aging, alcohol, and certain drugs impair liver function and can be a major cause of hormone imbalance in aging men. Heavy alcohol intake increases estrogen in men and women (54, 246, 285). Obesity Fat cells create aromatase enzyme and especially contribute to the buildup of abdominal fat (241, 242). Low testosterone allows the formation of abdominal fat (47, 239, 248), which then causes more aromatase enzyme formation and thus even lower levels of testosterone and higher estrogen (by aromatizing testosterone into estrogen). It is especially important for overweight men to consider hormone modulation therapy. Zinc Deficiency Zinc is a natural aromatase enzyme inhibitor (247). Since most Life Extension Foundation members consume adequate amounts of zinc (30-90 mg a day), elevated estrogen in Foundation members is often caused by factors other than zinc deficiency. Lifestyle Changes Lifestyle changes (such as reducing alcohol intake) can produce a dramatic improvement in the estrogen-testosterone balance, but many people need to use aromatase-inhibiting agents to lower estrogen and to improve their liver function to remove excess SHBG. Aromatase converts testosterone into estrogen and can indirectly increase SHBG. SHBG binds to free testosterone and prevents it from exerting its biochemical effects in the body. CORRECTING A HORMONE IMBALANCE Step 1- Blood Testing Step 2- Interpretation Blood Test Results Step 3-When Results Are Not Optimal A male hormone imbalance can be detected through use of the proper blood tests and can be corrected using available drugs and nutrients. The following represents a step-by-step program to safely restore youthful hormone balance in aging men: Step 1: Blood Testing The following initial blood tests are recommended for any man over age 40: Complete blood count and chemistry profile to include liver-kidney function, glucose, minerals, lipids, and thyroid (TSH) Free and Total Testosterone Estradiol (estrogen) DHT (dihydrotestosterone) DHEA PSA Homocysteine Luteinizing hormone (LH) (optional) Sex Hormone Binding Globulin (SHBG) (optional) Step 2: Interpretation of Free Testosterone, Estrogen, and Total Testosterone Blood Test Results Free Testosterone Estrogen Total Testosterone One can easily determine if they need testosterone replacement or estrogen suppression by adhering to the following guidelines: Free Testosterone Free testosterone blood levels should be at the high-normal of the reference range. We define high-normal range as the upper one third of the reference range. Under no circumstances should free or total testosterone be above the high end of the normal range. What too often happens is that a standard laboratory "reference range" deceives a man (and his physician) into believing that proper hormone balance exists because the results of a free testosterone test fall within the "normal" range. The following charts show a wide range of so-called "normal" ranges of testosterone for men of various ages. While these normal ranges may reflect population "averages," the objective for most men over age 40 is to be in the upper one-third tes-tosterone range of the 21- to 29-year-old group. Based on the following reference range chart from LabCorp, this means that optimal free testosterone levels should be between 21-26.5 nanogram/dL in aging men. Reference Intervals for Free Testosterone from LabCorp20-29 years9.3-26.5 picogram/mL30-39 years8.7-25.1 picogram/mL40-49 years6.8-21.5 picogram/mL50-59 years7.2-24.0 picogram/mL60+ years6.6-18.1 picogram/mL An example of how this chart can be deceptive would be if a 50-year-old man presented symptoms of testosterone deficiency (depression, low energy, abdominal obesity, angina, etc.), but his blood test revealed his free testosterone to be 9 picogram/mL. His doctor might tell him he is fine because he falls within the normal "reference range." The reality may be that to achieve optimal benefits, testosterone levels should be between 21-26.5 picogram/mL. That means a man could have less than half the amount of testosterone needed to overcome symptoms of a tes-tosterone deficiency, but his doctor will not prescribe testosterone replacement because the man falls within the "average" parameters. That is why it is so important to differentiate between "average" and "optimal." Average 50-year-old men often have the symptoms of having too little testosterone. Yet since so many 50-year-old men have lower than desired testosterone levels, this is considered to be "normal" when it comes to standard laboratory reference ranges. The Life Extension Foundation would like to point out that there is disagreement between clinicians and laboratories on the best method for measuring tes-tosterone status. There are different schools of thought as to which form of testosterone should be measured and which analytical procedure provides the most accurate assessment of metabolic activity. To illistrate this point, the reference values for measuring free testosterone from Quest Diagnostics follow: Adult Male (20-60+ years):1.0-2.7%50-210 pg/mLOptimal Range:150-210 pg/mL for aging men without prostate cancer. We believe that direct testing for free testosterone is the best way to test for testosterone activity, as free testosterone is active testosterone and consists of only 1-2% of total testosterone. Total testosterone can be good for general testing. The four main methods presently used for analyzing free testosterone are: Direct, Free Testosterone by Direct Analog/Radioimmunoassay (RIA) Testosterone Free by Ultrafiltration (UF) Testosterone Free by Equilibrium Tracer Dialysis (ETD) Testosterone Free and Weakly Bound by Radioasssay (FWRA) The latter three test methods are older, more complicated methods that are technically demanding. The direct RIA test has a number of commercial test kits available, and they are better used in today's automated equipment, making this test less tedious and requiring a smaller (less) sample. These advantages have convinced many laboratories and clinics to prefer direct RIA testing for free testosterone. The Life Extension Foundation agrees with this assessment, and therefore uses and recommends the direct free testosterone test with the above-mentioned reference levels. Consequently, if your doctor tests your free tes-tosterone, be sure you know the analytical method used. If your test results have a reference range as follows, you have probably been tested with one of the other test methods: Male Reference Range Test Type66-417 nanogram/dL FWRA12.3-63% %FWRA5-21 nanogram/dL UF or ETD50-210 picogram/mL UF or ETD1.0-2.7% % of free by UF or ETD No matter what test method is used to determine your free testosterone status, the optimal level (where you want to be) is in the upper one-third of normal for a 20-29 year old male. Estrogen Estrogen (measured as estradiol) should be in the mid- to lower-normal range. If estradiol levels are in the upper one-third of the normal reference range, or above the normal reference range, this excessive level of estrogen should be reduced. Labcorp lists a reference range of between 3-70 picogram/mL for estradiol while Quest states a reference range of between 10-50. For optimal health, estradiol should be in the range of 10-30 picogram/mL for a man of any age. The fact that most aging men have too much estrogen does not mean it is acceptable for a man to have low estrogen. Estrogen is used by men to maintain bone density, and abnormally low estrogen levels may increase the risk for prostate cancer and osteoporosis. The objective is to achieve hormone balance, not to create sky-high testosterone levels without enough estrogen. The problem is that, if we do nothing, most men will have too much estrogen and far too little testosterone. Total Testosterone Some men have their total testosterone measured. Standard reference ranges are between 241-827 nanograms/dL for most laboratories. Many older men are below 241. Optimal levels of total testosterone for most men are between 500-827 nanograms/dL. If your levels are lower than 500 nanograms/dL or even a little higher and you still have symptoms, you should check your free testosterone by the Direct (RIA) method. For other hormone tests, the following are considered to be optimal: Where You Want to Be CommentPSA Under 2.6 ng/mL (optimal range) Standard reference range is up to 4, but if your level is persistently 2.6 or above, have a blood test to measure the percentage of free vs. bound PSA and a digital rectal exam to help rule out prostate cancer.DHEA 400-560 mcg/dL (optimal range) For older men, standard DHEA ranges are very low. It is important for men without prostate cancer to restore them to the youthful range (400-560).DHT 20-50 nanogram/dL (optimal range)Reference range is 30-85. DHT is 10 times more androgenic than testosterone and has been implicated in prostate problems and hair loss.Luteinizing hormone (LH) Age 20-70: 1.5-9.3 mIU/mL 70+: 3.1-34.6 mIU/mL (standard reference ranges) Under 9.3 mIU/mL (optimal range)If these levels are high, it is an indication of testicular testosterone production deficiency. LH tells the testes to produce testosterone. If there is too little testosterone present, the pituitary gland secretes more LH in a futile effort to stimulate testicular testosterone production. Testosterone replacement therapy should suppress excess LH levels. Low LH can also be a sign of estrogen overload, since too much estrogen can suppress LH activity. This could mean using an estrogen blocker like Arimidex could solve a testosterone deficiency problem.Sex Hormone Binding Under 30 nanomoles/L (optimal range) Reference range is 13-71 nanomole/L. Excessive binding inactivates testosterone (297). Referring to Table 1, there are five possible reasons why free testosterone levels may be low-normal (below the upper third of the highest number of the reference range): Too much testosterone is being converted to estradiol by excess aromatase enzyme and/or the liver is failing to adequately detoxify surplus estrogen. Excess aromatase enzyme and/or liver dysfunction is likely the cause if estradiol levels are over 30. emember, aromatase converts testosterone into estradiol, which can cause estrogen overload and testosterone deficiency. Too much free testosterone is being bound by SHBG (sex hormone binding globulin). This would be especially apparent if total testosterone levels were in the high normal range, while free testosterone was below the upper one-third range. The pituitary gland fails to secrete adequate amounts of luteinizing hormone (LH) to stimulate testicular production of testosterone. Total testosterone in this case would be in the bottom one-third to one-half range. (On LabCorp's scale, this would be a number below 241-500 ng/dL.) The testes have lost their ability to produce testosterone, despite adequate amounts of the testicular-stimulating luteinizing hormone. In this case, LH would be above normal, and total testosterone would in very low normal or below normal ranges. Inadequate amounts of DHEA are being produced in the body. (DHEA is a precursor hormone to tes-tosterone and estrogen) (250). Step 3: What to Do When Results Are Less Than Optimal If estradiol levels are high (above 30), total testosterone is mid- to high-normal, and free testosterone levels are low or low-normal (at the bottom one third of the highest number on the reference range), you should: Make sure you are getting 80 mg a day of zinc. (Zinc functions as an aromatase inhibitor for some men.) Consume 400 mg of indole-3-carbinol to help neutralize dangerous estrogen metabolites. Cruciferous vegetables, such as broccoli and cauliflower, can also stimulate the liver to metabolize and excrete excess estrogen. Reduce or eliminate alcohol consumption to enable your liver to better remove excess estrogens (refer to the Liver Degenerative Disease protocol to learn about ways to restore healthy liver function). Review all drugs you are regularly taking to see if they may be interfering with healthy liver function. Common drugs that affect liver function are the NSAIDs: ibuprofen, acetaminophen, aspirin, the "statin" class of cholesterol-lowering drugs, some heart and blood pressure medications, and some antidepressants. It is interesting to note that drugs being prescribed to treat the symptoms of testosterone deficiency such as the statins and certain antidepressants may actually aggravate a testosterone deficit, thus making the cholesterol problem or depression worse. Lose weight. Fat cells, especially in the abdominal region, produce the aromatase enzyme, which converts testosterone into estrogen (242). Take a combination supplement providing a flavonoid called chrysin (1000 mg) along with piperine (10 mg) to enable the chrysin to be absorbed into the blood stream. Chrysin has been shown to be a mild aromatase inhibitor. This combination of chrysin and peperine can be found in a product called Super MiraForte. If all of the above fail to increase free testosterone and lower excess estradiol, ask your doctor to prescribe the potent aromatase inhibiting drug Arimidex (anastrozole) in the very low dose of 0.5 mg twice a week. Arimidex is prescribed to breast cancer patients at the dose of 1-10 mg a day. Even at the higher dose prescribed to cancer patients, side effects are rare. In the minute dose of 0.5 mg twice a week, a man will see an immediate drop in estradiol levels and should experience a rise in free testosterone to the optimal range. 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 because 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 dihydrotes-tosterone. 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 third of the reference range or below normal, and free testosterone is low, and estradiol levels are under 30, you should Initiate therapy with the testosterone patch, pellet, or cream. Do not use testosterone injections or tablets. or 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 2-3 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. 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 30-45 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 third of the highest number in the reference range) and estradiol (not more than 30), make sure your blood is tested every 30-45 days for the first 5 months. Test every 6 months thereafter for free testosterone, estradiol, and PSA. For men in their 40s-50s, correcting the excess level of estradiol is often all that has to be done. THERAPIES "Andro" Supplements Testosterone Patches, Creams, Pellets, and Tablets Natural Testosterone-Boosting/Estrogen-Suppressing Approaches "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. 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 Patches, Creams, Pellets, and Tablets 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 tes-tosterone 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 test and digital rectal exam are recommended for men over age 40. While restoring free testosterone to healthy physiological levels does not cause prostate cancer, it can induce existing prostate cancer cells to proliferate faster.