Hormone Replacement Therapy (HRT) – Part 2

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. New findings have shed light on subtle hormone imbalances in obese men that are of borderline character and often fall within the normal laboratory reference range. Boosting testosterone levels seems to decrease the abdominal fat mass, reverse glucose intolerance, as well as lipoprotein abnormalities in the serum. Further analysis has also disclosed a regulatory role for testosterone in counteracting visceral fat accumulation. Longitudinal epidemiological data demonstrate that relatively low testosterone levels are a risk factor for development of visceral obesity. (7,237)

One study showed that serum estrone and estradiol was twofold elevated in one group of morbidly obese men. Remember, fat cells synthesize the aromatase enzyme, and this causes 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 or carbohydrate meals had no effect on serum hormone levels, but a fat-containing meal reduced free testosterone levels for 4 hours. (243)

So obese men suffer from testosterone deficiency caused by excess aromatase enzyme being produced in fat cells and also from the fat they consume in their diet. (240) The resulting hormone imbalance (too much estrogen and not enough free testosterone) in obese men partially explains why so many are impotent, and suffer from a wrath of premature degenerative diseases.(45)

Factors Causing the Estrogen-Testosterone Imbalance in Men

If your blood tests reveal high estrogen and low testosterone, 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. (279) 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, especially 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 to 90 mg/day), elevated estrogen in Foundation members is often caused by factors other than zinc deficiency.

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. Remember, aromtase converts testosterone into estrogen and can indirectly increase SHBG. SHBG binds to free testosterone and prevents its from exerting its biochemical effects in the body.

Correcting A Hormone Imbalance

A male hormone imbalance is correctable by utilizing the proper blood tests and 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, thyroid (TSH) etc.)
Free and Total Testosterone
Estradiol (estrogen)
Luteinizing hormone (LH)

Step # 2: Interpretation of Estrogen-Testosterone ratio and Free Testosterone Test Results

One of the difficulties in offering standardized interpretations at this time is that blood testing laboratories are using differing test methodologies and reference ranges for testosterone and other hormones.

When interpreting serum testosterone-estrogen (estradiol) levels, the following are basic guidelines:

Free testosterone should be at the high normal reference range. We define high normal range as the upper one-third of the highest number on the reference range. Under no circumstances should free or total testosterone be above the high normal range.
Estrogen (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.

What is most surprising is how standard laboratory “reference ranges” can fool a man (and his physician) into believing he has proper hormone balance simply because he falls within the “normal” range.

The following charts compare the conventional normal ranges for a man aged 20-49 and what the optimal ranges should be for most men over age 40:

Reference Ranges used by: LabCorp and Life Extension’s Laboratory Hormone Conventional Normal Range Optimal Range
Free Testosterone 12.4- 40 26- 40 pg/mL
Estradiol 0-44 15-30 pg/mL
Total Testosterone 300 – 1000 600-1000 ng/dl

Reference Ranges used by SmithKline: Hormone Conventional Normal Range Optimal Range
Free Testosterone 34-194 128-194 pg/mL
Estradiol 0-50 15-30pg/mL
Total Testosterone 194-833 500-833 ng/dl

Reference Ranges used by Quest Laboratories Hormone Conventional Normal Range Optimal Range
Free Testosterone 50-210 138-210 pg/mL
Estradiol 0-60 15-30 pg/mL
Total Testosterone 260-1000 500-1000 ng/dl

Please remember that the conventional “normal” ranges stated above are for men aged 20-49. Conventional medicine does not expect a man over age 50 to have much testosterone, so the laboratories use a much lower reference range for men over 50. For instance, the reference range used by LabCorp for men over 50 for free testosterone is only 10.8 to 24.6, yet we have strong reason to believe the optimal range for a man over 50 should be 26 to 40. This low reference range shows how conventional medicine expects and accepts that a man over 50 will have sub-optimal free testosterone levels (and suffer all of the negative consequences of a testosterone deficiency we have discussed so far.) We presume that no one reading this article wants to be in the “normal” range of free testosterone for men over age 50.

Also not that these reference ranges indicate that it can be normal for a man to have no estrogen. The fact that most aging men have too much estrogen does not mean it is acceptable for a man to have NO (or virtually no) estrogen. Estrogen is used by men to maintain bone density and abnormally low estrogen levels may increase the risk for prostate cancer and osteoporosis. (37,117,132,184,249) Please remember the objective is hormone balance, not to create sky-high testosterone levels and not enough estrogen. The problem is that if we do nothing, most men will have too much estrogen and far too little testosterone.

If free testosterone levels are low normal (below the upper third of the highest number of the reference range), there are five possible reasons for this:

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 case if estradiol levels are over 30. Remember, 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). (281-284) This would be especially apparent if total testosterone levels were in the high normal range, while free testosterone was under the upper one-third range (in the case of LabCorp, this would mean a number below 26)

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 number. (in the case of LabCorp, this would be a number below 333-500)

The testes have lost their ability to produce testosterone, despite adequate amounts of the testicular stimulating hormone, 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 DHEA ( and estrogen). (250)

Step# 3: What To Do When Results Are Less Than Optimal

(A) If estradiol levels are high (above 30), total testosterone is mid to high normal and free testosterone levels are low or low normal (bottom one-third of the highest number on the reference range), you should:

(1) Make sure you are getting 80-90 mg a day of zinc. Zinc functions as an aromatase inhibitor for some men.

(2) Consume 110 mg of soy isoflavones (phytoestrogens) each day. High levels of phytoestrogens compete with estradiol on cell receptor sites and stimulate the liver to remove estrogens from the blood. Cruciferous vegetables such as broccoli and cauliflower can also promote the liver to metabolize and excrete excess estrogen

(3) Reduce or eliminate alcohol consumption to enable your liver to better remove excess estrogens. Refer to the Foundation’s Liver Degeneration protocol to learn about ways to restore healthy liver function.

(4) 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 anti-depressants. It is interesting to note that drugs being prescribed to treat the symptoms of testosterone deficiency such as the statins and certain anti-depressants may actually aggravate a testosterone deficit, thus making the cholesterol problem or depression worse!

(5) Lose weight. Fat cells, especially in the abdominal region, produce aromatase enzyme, which converts testosterone into estrogen. (242)

(6) If all of the above fail to increase free testosterone and lower excess estradiol, then ask your doctor to prescribe the potent aromatase inhibiting drug Arimidex (anastrozole) in the very low dose of one-half (0.5 mg) mg, twice a week. Arimidex is prescribed to breast cancer patients at the dose of 1 to10 mg a day. Even at the high 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.

(B) 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:

(1) 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.

(2) 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 block 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 an effect of blocking the oxidation of testosterone to androstenedione, a potent androgen that has been implicated in the development of prostate disease. (253)

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

(1) See if your luteinizing hormone (LH) is below normal. If LH is low, your doctor can prescribe an individual dose of chorionic gonadotropin (***) hormone for injection . Chorionic gonadotropic hormone functions similar to LH and can re-start testicular production of testosterone. Your doctor can instruct you how to use tiny 30-gauge needles to inject yourself two to three times a week. (Editor’s note: Some scientists think *** may cause cancer. If this concerns you, consider using a testosterone patch, cream, or pellet.)

(2) After one month on chorionic gonadotropic hormone, a blood test can determine if 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 30-45 days for the first 5 months to make sure the exogenous testosterone you are putting into your body is following a healthy metabolic pathway, i.e. it is raising your levels of free testosterone, but not increasing estradiol levels beyond 30.

(D) If total testosterone remain low despite several months of chorionic gonadotropic hormone therapy, this indicates that your testicles are not capable of producing testosterone. In this case, initiate therapy with the testosterone patch, pellet or cream. Do not use testosterone injections or tablets. Before initiating testosterone repla***ent 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 putting into your body is following a healthy metabolic pathway and not causing a flare up of an under lying prostate cancer. The objective is to raise your levels of free testosterone to the upper third of the reference range, but not increase estradiol levels beyond 30.

Remember, 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. Then test every 6 months thereafter for free testosterone, estradiol, PSA, etc. 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 then later in life, may need to use a testosterone patch, cream or pellet.

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 exogenous testosterone being converted 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 backed up 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 case doubt. A study in the Journal of the American Medical Association (JAMA) reported on an 8-week study showing that androstenedione supplements increased estrogen levels in 30 men. 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. (258)

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. Here is a listing of some of the synthetic testosterone drugs to avoid using on a long-term basis:

Testosterone propionate , cypionate , or enanthate
Just because testosterone is called a “drug’ does not mean it is not the same natural hormone your body produced. Scientists learned how to make the identical testosterone your body produces decades ago, 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. Here is a listing of currently available “natural” testosterone drugs:

Androderm Transdermal System (Smith Kline Beecham’s testosterone “patch”
Testoderm Transdermal System (Alza’s testosterone “patch” )
Testosterone creams, pellets and sub-lingual tablets (available from compounding pharmacies)
Both the synthetic and natural testosterone drugs require a prescription, and this prescription should only be written when 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 are exposed to children, you may want to avoid testosterone creams as there is one report of a father causing a young male child to go through pre-mature puberty because the child made contact with the testosterone cream on the father’s body and on weight lifting equipment in the home. This unique case is a testament to the powerful effects that testosterone exerts in the body

Caution: DO NOT REPLACE TESTOSTERONE 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 state 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 put on testosterone ablation therapy often temporarily suffer 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 is recommended for men over age 40. While restoring free testosterone to healthy physiological levels (25 to 40 pg/mL) does not cause prostate cancer, it can induce existing prostate cancer cells to proliferate faster.

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 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. Followup testing on testosterone, estrogen, and PSA are needed to rule out occult prostate cancer and to fine tune your program. It’s possible that testosterone patches, creams, etc. can increase testosterone too much. In this case, blood or saliva testing could save you money be allowing you to use less testosterone drug.

There are now under development, natural dietary supplements 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.

More Information

Over the last year, three new books have been written about testosterone repla***ent therapy.

The best place to read about actual case histories of men who successfully used hormone modulation is Dr. Eugene Shippen’s book the Testosterone Syndrome. Dr. Shippen’s book provides many interesting details that could not fit into this concise protocol. Dr. Jonathan Wright’s book called Maximize Your Vitality and Potency contains historical and more technical data about the benefits of testosterone that again, could not be fit into this concise protocol. Dr. Karlis Ullis’ book Super T deals primarily with dietary and supplement modifications related to testosterone deficiency.

The Testosterone Syndrome, Eugene Shippen, M.D., cover price: $21.95, member price: $15.00. Maximize Your Vitality and Potency, Jonathan, Wright, M.D., cover price: $14.95, member price: $11.00.

Super T , Karlis, Ullis, M.D., cover price: $12.00, member price: $8.50.

You can expect updates to this protocol in future issues of Life Extension Magazine as more information becomes available. The Foundation will be extensively monitoring the effects of this program based on reports from clinical physicians and Foundation members. As always, worldwide data base searches will routinely be conducted to uncover new studies relating to the effects of hormone modulation and aging.


Due to the highly controversial nature of this article, we have taken the unprecedented step of publishing over 180 pages of scientific abstracts on our website ( www.lef.org) that are numerically matched to the statements made in this article. This may be the first time such a massive undertaking has been done, and it reflects the urgent need to convey this information to skeptical physicians so that they will prescribe testosterone and aromatase-inhibiting drugs to Foundation members 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 testosterone HT 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.”
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.”
Cancer Epidemiol. Biomarkers Prev. (1996 Aug; 5(8):621-5)

Study conducted at: Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu 96817, USA.

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.”
Journal of the American Medical Association (JAMA) 1996 Dec.18;276(23):1904-6

Study conducted at: Division of Urology, Beth Israel Hospital, Harvard Medical School, Boston, Mass. 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.”
Cancer Epidemiology and Biomarkers Prev. (1998 Dec;7(12):1069-74)

Study conducted at: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 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.”
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 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.”
Cancer Research (1988 June 15;48(12):3515-7)

Study conducted at: Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu 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 behaviour 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).”
European Journal of Cancer Prev., (1992 April;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.”
Cancer Epidemiology Biomarkers Prev. (1993 Jan-Feb;2(1):27-32 )

Study conducted at: National Cancer Institute, Division of Cancer Etiology, Bethesda, Maryland 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.”
Cancer Research (1991 July 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 tumour 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 tumours. 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, tumour stage and ploidy. The testosterone/DHT ratio tended to be higher in patients with more advanced tumours. SHBG levels were lower in patients with cancer than in controls but the differences were not statistically significant. There were no systematic variations of tumour stage, grade and ploidy. Within a group, DHT levels tended to be lower among cases and in those with more advanced tumours. No systematic variation were found in the levels of testosterone or SHBG.”
British Journal of Urology (1996 March;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 brothers with or without prostatic cancer than among nonbrothers”
Prostate (1985; 6(2):121-8)

Study 12: ” Baseline sex hormone levels were measured in 1008 men ages 40-79 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.”
Cancer Research (1990 Jan 1;50(1):169-73)

Study conducted at: Department of Community and Family Medicine, University of California San Diego, La Jolla 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 non-significantly lower among cases.”
British Journal of Cancer 1993 July;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.
Prostate 1987;11(2):171-82

Study conducted at: Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, 2751.

Study 15: “The prostate cancer patients had a slightly lower mean free testosterone and mean estradiol/free T ratio than the BPH patients. The mean estradiol/free testosterone ratio was significantly higher in the BPH 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 BPH patients may act as a protective factor against prostatic cancer.
Prostate 1983;4(3):223-9

Study 16: ” A 4-fold 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 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
Journal of Clinical Endocrinology and Metabolism (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 yr 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.
European Journal of Cancer Clinical Oncology (1984 April ;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.
candinavian Journal of Urology and Nephrology Supplmental (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.
AMA, 1995 Nov; 87(11):813-9

Study conducted at: Department of Radiation Oncology, Michael Reese Hospital, Center for Radiation Therapy, University of Chicago, Illinois.

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 (BPH). 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.
Prostate Supplemental (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 2-4 weeks in 10 hypogonadal men undergoing treatment with exogenous testosterone, delivered as testosterone enanthate injection or by testosterone patch. A 2-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.
Journal of Surgical Oncology (1995 Aug;59(4):246-50 )

Study conducted at: Department of Surgery, Walter Reed Army Medical Center, Washington, D.C. 20307-5001.

The 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 nonsignificantly inversely with the disease.
Cancer Causes Control 1997 July;8(4):632-6

Study conducted at: Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, Massachusetts 02115.

Studies Indicating 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." Journal of the National Cancer Institute (1996 Aug. 21;88(16):1118-26 ) Study conducted at: Department of Medicine, Brigham and Women's 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 adreno-corticotropic 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 tE1 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.
British Journal of Urology (1997 March;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.
Journal of Andrology (1997 Sep-Oct;18(5):495-500)

Study conducted at: Division of Urology, Duke University Medical Center, Durham, North Carolina 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.”
Urology (1999 Feb;53(2):423-4 )

Study conducted at: Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts 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.”
Journal of Steroid Biochemistry (1989 July;33(1):19-24 r.)

Study conducted at: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City 84132.

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