Fall Skin Care Sale

Life Extension Magazine

LE Magazine December 2008
Reports

Destroying the Myth About Testosterone Replacement and Prostate Cancer

By Abraham Morgentaler, MD, Facs Introduction By William Faloon
The Memorial Sloan Kettering Experience

The Memorial Sloan Kettering Experience

I was still giddy when I decided to look up the article detailing the experience of testosterone administration to men with metastatic disease from the Memorial Sloan Kettering Cancer Institute, published in 1981 by the urologic giant of his day, Willet Whitmore, and his colleague, Jackson Fowler. The short summary of the paper was quite damning. Over a course of eighteen years, fifty-two men with metastatic disease had undergone treatment with daily T injections, usually as a last-gasp treatment for their cancer. Of these fifty-two men, forty-five had experienced an “unfavorable response,” most within the first month of treatment.

This seemed pretty grim. Maybe Huggins had been right after all, despite basing his conclusions on a solitary patient. But then I discovered something equally shocking in the fine print of this article. Of the fifty-two men studied, all but four had already been treated with castration or estrogen treatment to lower testosterone. And of these four previously untreated men, one had an early, unspecified unfavorable response, while the remaining three men continued to receive daily T injections for 52, 55, and 310 days without apparent negative effects. In fact, one of these men was reported to have had a “favorable response” to T administration.

Drs. Fowler and Whitmore were impressed by the difference in outcomes for the untreated group of four men compared with the men who had already undergone hormonal treatment to lower testosterone. To explain the lack of negative effects on the untreated men, the authors postulated the following: “Normal endogenous testosterone levels may be sufficient to cause near maximal stimulation of prostatic tumors.” In other words, raising testosterone levels beyond the normal range did not seem to cause any increased cancer growth, even in men with metastatic disease!

This important concept was lost in the headline of the study, which clearly indicated that giving testosterone to men with prostate cancer was associated with rapid onset of negative consequences in most men. One had to read the article closely to learn that the headline applied only to men who had been previously castrated. Although this article has been cited for many years as evidence that T administration causes rapid and near-universal growth of prostate cancer (PCa), the authors in fact clearly made the point that the worrisome effects of T administration did not appear to occur in their small group of men without prior hormonal treatment.

Testosterone Flare

It had been an amazing day in the library, which had long since turned to night. My head was spinning, but I wanted to tackle the last hurdle, the problem of testosterone flare. In the early 1980s, medications were developed to replace the need for surgical removal of the testicles for men with advanced prostate cancer. These medications are called LHRH agonists, and they continue to be used to this day. LHRH injections cause T concentrations to increase by 50 percent or more for seven to ten days, after which testosterone levels fall rapidly to castrate levels. This transient rise in testosterone is called testosterone flare.

Testosterone Flare

Not long after LHRH agonists began to be used, there were reports of complications occurring after men began these treatments, and these complications were attributed to testosterone flare causing rapid growth of prostate cancer. These complications included the inability to urinate, worsening of bone pain, or, in the most tragic cases, paralysis due to collapse of a vertebra in which the cancer had eaten away the bone. As a result, for the last twenty years, it has been routine to add medications to block testosterone flare when starting a patient on treatment with LHRH agonists.

That night in the basement of Countway Library, I pulled all the original studies I could find of LHRH agonists, as well as reports of bad outcomes due to the flare. As I read, two things became apparent. First, many of the bad outcomes attributed to testosterone flare occurred a month or more after initiation of treatment. This meant that these complications occurred not when testosterone levels were high, but when testosterone levels had already dropped for some time to castrate levels.

Second, out of the substantial literature on LHRH agonists and prostate cancer, I could find only two articles that actually measured and reported PSA levels during the time of the testosterone flare. And here was the kicker: both articles showed absolutely no change in mean PSA values during the time of the testosterone flare! Curiously, neither article so much as mentioned this result.

PSA is an excellent indicator of prostate cancer growth. The fact that PSA did not rise in these men during the testosterone flare strongly suggested that the cancers did not grow during this time. Perhaps the complications attributed to testosterone flare were nothing more than the cancer progression that would have happened without any treatment at all.

It had been quite a day and night in the Countway Library. I left with my head spinning and a feeling that I had stumbled onto something very important. It was like the children’s story The Emperor’s New Clothes—we see what we want to see. And for two-thirds of a century, it had been assumed that raising testosterone increased prostate cancer growth. But maybe the emperor was naked.

Even in men with metastatic disease, there was no evidence I could find that raising testosterone made prostate cancer grow more than it would have anyway. Shockingly, the very publications cited so regularly to demonstrate a dangerous relationship between testosterone and prostate cancer contained evidence that this was not true.

The Paradox Resolved

Still, I was worried, because there was a bothersome unresolved paradox to explain. For decades, the storyline was that lowering testosterone levels caused prostate cancer to shrink away and raising testosterone levels caused it grow. The second part of this story was now seriously in doubt, yet the first part was obviously correct. In my own practice, I had seen the beneficial effects of lowering testosterone levels many times over in men with advanced prostate cancer. This part of Dr. Huggins’s work was indisputable. But if lowering testosterone levels caused these cancers to shrink, how was it possible that raising testosterone levels did not cause the cancers to grow? This was a paradox that needed to be solved if physicians were to accept the possibility that testosterone therapy may not increase the risk of prostate cancer.

The Paradox Resolved

The answer turns out to be not all that complicated. All the reports of testosterone causing rapid growth of prostate cancer occurred in men who already had extremely low testosterone levels, due to castration or estrogen treatment. Once we get beyond the near-castrate range, it is hard to find any evidence that changes in T concentrations matter at all to prostate cancer. This is essentially what Drs. Fowler and Whitmore described in their 1981 article when they suggested that “near maximal” growth of prostate cancer is provided by naturally occurring T concentrations.

The experimental proof of this concept was provided by a landmark article published in 2006 using much more sophisticated means. In this study by Leonard Marks and colleagues, men with low testosterone received injections of testosterone or a placebo every two weeks for a total of six months. At the beginning and end of the study, measurements of testosterone and DHT (the more active form of testosterone within prostate tissue) were obtained from the blood and also from the prostate itself. The results showed that although blood concentrations of testosterone and DHT rose substantially in the T injection group, as expected, the concentration of testosterone and DHT within the prostate itself did not change at all and was similar to the group that received placebo injections. In addition, biochemical markers of prostate cell growth also did not change with T injections.

This study showed in elegant fashion that raising testosterone levels in the blood did not raise testosterone levels within the prostate. It is as if once the prostate has been exposed to enough testosterone, any additional testosterone is treated as excess and does not accumulate in the prostate. In technical terms, we say the prostate has been saturated with regard to testosterone. And it is this saturation that resolves the paradox of testosterone and prostate cancer.

Saturation explains the paradox in this way. At very low levels of T, near the castrate range, prostate growth is very sensitive to changes in T concentration. Thus, severely lowering testosterone will definitely cause prostate cancer to shrink; adding testosterone back will cause the cancer to regrow. However, once we get above the point where the prostate is saturated with testosterone, adding more testosterone will have little, if any, further impact on prostate cancer growth. Experimental studies suggest the concentration at which this saturation occurs is quite low.

In other words, the old analogy I learned in training was false. Testosterone is not like food for a hungry tumor. Instead, a much better analogy is, “Testosterone is like water for a thirsty tumor.” Once the thirst has been satisfied, prostate tumors have no use for additional testosterone. And the vast majority of men with low testosterone appear to have prostates that are not particularly thirsty.

A New Concern: Prostate Cancer and Low testosterone

I no longer fear that giving a man testosterone therapy will make a hidden prostate cancer grow or put him at increased risk of developing prostate cancer down the road. My real concern now is that men with low testosterone are at an increased risk of already having prostate cancer.

When my colleagues and I published our results in 1996 from prostate biopsies in men with low testosterone and PSA of 4.0 ng/mL or less, the 14 percent cancer rate was several times higher than any published series of men with normal PSA. In 2006, Dr. Rhoden and I published a larger study of prostate biopsies performed in 345 men. The cancer rate of 15 percent in this group was very similar to the first study. But whereas the cancer rate in 1996 was much higher than anything published to that date in men with PSA of 4.0 ng/mL or less, in 2006 the perspective had changed due to an important study called the Prostate Cancer Prevention Trial.

A New Concern: Prostate Cancer and Low Testosterone

In that study, the cancer rate among men with a PSA of 4.0 ng/mL or less was also 15 percent. Because this value is identical to what we had found in our patients with low testosterone, it was suggested that the cancer rate in men with low testosterone is the same as the normal population—neither higher nor lower. However, the average age of men in our study was a decade younger than the men studied in the Prostate Cancer Prevention Trial (fifty-nine versus sixty-nine years). Almost half the men in the other study were seventy years or older, and age is the greatest risk factor we know for prostate cancer. The way I look at these numbers is that men with low testosterone have a cancer rate as high as men with normal T who are a decade older.

More importantly, in our study of 345 men, we found that the degree of testosterone deficiency correlated with the degree of cancer risk. Men whose testosterone levels were in the bottom third of the group were twice as likely to have cancer diagnosed on biopsy as men in the upper third. This finding adds to the concern that low testosterone is a risk factor for prostate cancer.

There is now additional data from around the world associating low testosterone and worrisome features of prostate cancer. For example, low testosterone is associated with more aggressive tumors. In addition, men with low testosterone appear to have a more advanced stage of disease at the time of surgical treatment.

Whereas I originally began to perform prostate biopsies in men with low testosterone because I was worried that treatment might cause a hidden cancer to grow, I now perform biopsies in these men because I am concerned they might have an increased risk of cancer. This risk is approximately one in seven for men with PSA values less than 4 ng/mL.

Because prostate cancer tends to be curable when caught early, I feel I’ve done these men a service by finding their cancers before they have an abnormal PSA or DRE. With today’s ability to monitor men with prostate cancer, not all of these men will necessarily require treatment. But the ones who have evidence of more aggressive tumors should definitely have an advantage by having their diagnosis made early.

The Evidence as it Now Stands

For over sixty-five years, there has been a fear that testosterone therapy will cause new prostate cancers to arise or hidden ones to grow. Although no large-scale studies have yet been performed to provide a definitive verdict on the safety of testosterone therapy, it is quite remarkable to discover that the long-standing fear about testosterone and prostate cancer has little scientific support. The old concepts, taken as gospel, do not stand up to critical examination. I believe the best summary about the risk of prostate cancer from testosterone therapy, based on published evidence at the time this book is written, is as follows:

Low blood levels of testosterone do not protect against prostate cancer and, indeed, may increase the risk.

High blood levels of testosterone do not increase the risk of prostate cancer.

Treatment with testosterone does not increase the risk of prostate cancer, even among men who are already at high risk for it.

In men who do have metastatic prostate cancer and who have been given treatment that drops their blood levels of testosterone to near zero, starting treatment with testosterone (or stopping treatment that has lowered their testosterone to near zero) might increase the risk that residual cancer will again start to grow.

Prostate cancer with infiltration into bladder, lymph nodes, and urethra.
Prostate cancer with infiltration into bladder, lymph nodes, and urethra.

One of the most important and reassuring studies regarding testosterone and prostate cancer was an article published in the Journal of the National Cancer Institute in 2008, in which the authors of eighteen separate studies from around the world pooled their data regarding the likelihood of developing prostate cancer based on concentrations of various hormones, including testosterone. This enormous study included more than 3,000 men with prostate cancer and more than 6,000 men without prostate cancer, who served as controls in the study. No relationship was found between prostate cancer and any of the hormones studied, including total testosterone, free testosterone, or other minor androgens. In an accompanying editorial, Dr. Carpenter and colleagues from the University of North Carolina School of Public Health suggest scientists finally move beyond the long-believed but unsupported view that high testosterone is a risk for prostate cancer.

More and more physicians are coming around to recognize that testosterone therapy is not a true risk for prostate cancer, but it can take many years to alter established beliefs. Don’t be surprised if your own doctor still raises this issue with you if you are considering testosterone therapy. If he objects to treating you for that reason, you should refer him to the article above, or one of the other review articles listed in the References at the back of this book. Even better, have him read this chapter!

Q. I’m fifty-three years old and I’ve been on testosterone therapy for two years, with good results. However, my father was diagnosed with prostate cancer at age seventy-five. Does this mean I need to stop testosterone?

A. There is a familial form of prostate cancer, but only in families in which prostate cancer occurs at age sixty-five or younger. Even in those families where a family member develops cancer at a young age, this does not necessarily mean that every other male in the family will develop cancer. Men with a family history of prostate cancer should be sure to have a yearly PSA and prostate exam. There is no need to discontinue testosterone treatment.

Q. My physician started me on testosterone, but I never had a prostate biopsy. I am sixty-four years old. Was this a mistake?

A. Because there is no evidence that testosterone treatment increases the risk of prostate cancer, it is fine to begin therapy as long as your PSA and DRE are normal. My own practice is to recommend prostate biopsy in men with low testosterone because our published data indicate there is an increased risk that cancer is already present in men with low testosterone, but this is by no means a standard recommendation yet among physicians.

Q. Why do you perform prostate biopsies on men with low testosterone if you don’t feel that testosterone treatment will make a hidden cancer grow?

A. Because so many men with prostate cancer will not die from it, even without treatment, there is a fair amount of controversy over how aggressive to be in making the diagnosis. My perspective is that it is worth knowing the diagnosis, whether or not one chooses to be treated immediately. And because low testosterone seems to represent a small but definite increased risk, I feel that biopsy in men over fifty with low testosterone is worthwhile.

Q. A man in my bowling league was started on testosterone treatment and then developed prostate cancer one year later. Doesn’t that show that testosterone is risky for prostate cancer?

A. If the wife of this man had switched to a new type of laundry detergent before the cancer was diagnosed, would we assume the cancer was caused by the detergent? Of course not. But we are predisposed to believe that testosterone therapy causes prostate cancer, so it is easy to hear a story like this and assume that testosterone therapy caused the cancer. Prostate cancer and testosterone therapy are both common in the United States, and both tend to occur in the same age range, so there will always be stories of men developing cancer some time after beginning testosterone therapy. If testosterone really made prostate cancers grow, then we should see high rates of cancer among men who start testosterone therapy. But we don’t. It’s false logic.

Q. Isn’t it true that all men would eventually get prostate cancer if they lived long enough? If so, why does it even matter if testosterone were to increase the risk of something that is inevitable anyway?

A. Men do get prostate cancer at an increasingly high rate as they age. And it is true that most men diagnosed with prostate cancer would never have a moment’s trouble from it, even if it were left untreated, because most of these cancers grow so slowly that other medical conditions eventually become more troublesome. Yet for those with more aggressive forms of prostate cancer, the danger is very real. The challenge is to identify men at risk, because even high-grade prostate cancer is curable when caught early.

Q. It took more than thirty years for scientists to learn that hormones were dangerous for women and caused breast cancer. Isn’t it possible we’ll eventually find out the same is true for testosterone and prostate cancer?

Abraham Morgentaler, MD
Abraham Morgentaler, MD

A. The fear that hormone therapy is dangerous in women is currently being reevaluated, and it appears to not be as dangerous as was originally proclaimed. More to the point, it is critical to understand that men are not women and that testosterone is not estrogen. Anyone, particularly a scientist, must always allow for the possibility that new information will one day change current views. But after so much research over so many decades, there is little reason to believe that testosterone therapy poses a major risk for prostate cancer. As a medical student once said to me, “If testosterone is really so dangerous for prostate cancer, why is it so hard to show it?”

Abraham Morgentaler, MD, is an associate clinical professor of urology at Harvard Medical School, and is the founder of Men’s Health Boston, a center focusing on sexual and reproductive health for men. He is the author of a number of popular books including The Male Body and The Viagra Myth.

Excerpted with permission from Testosterone for Life: Recharge Your Sex Drive, Muscle Mass, Energy and Overall Health by Abraham Morgentaler, MD, FACS. Published by McGraw-Hill.

If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.

References

Agarwal PK, Oefelein MG. Testosterone replacemen testosterone therapy after primary treatment for prostate cancer. J Urol. 2005 Feb;173(2):533-6.

Araujo AB, Kupelian V, Page ST, et al. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med. 2007;167:1252-60.

Bhasin S, Singh AB, Mac RP, Carter B, Lee MI, Cunningham GR. Managing the risks of prostate disease during testosterone replacement therapy in older men: recommendations for a standardized monitoring plan. J Androl. 2003;24:299-311.

Bhasin S, Storer TW, Berman N, et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. 1997;82:407-13.

Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56:1278-81.

Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate. 1995;27(1):25-31.

Cherrier MM, Craft S, Matsumoto AH. Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. J Androl. 2003;24:568-76.

Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999;84(10):3469-78.

English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina. Circulation. 2000;102(16):1906-11.

Gann PH, Hennekens CH, Ma J, et al. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88(16): 1118-26.

Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J. Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? J Urol. 2005 Feb;173(2):341.

Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metabol. 2001;86(2):724-31.

Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol. 2000;163: 824-7.

Hsing AW. Hormones and prostate cancer: what’s next? Epidemiologic Rev. 2001;23(1):42-58.

Huggins CB, Stevens RB, Hodges CV. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209.

Hwang TI, Chen HE, Tsai TF, Lin YC. Combined use of androgen and sildenafil for hypogonadal patients unresponsive to sildenafil alone. Int J Impot Res. 2006;18:400-4.

Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004 Sep;172(3):920-2.

Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in non-obese men. J Clin Endocrinol Metab. 2006;91:843-50.

Lazarou S, Morgentaler A. Hypogonadism in the man with erectile dysfunction: what to look for and when to treat. Curr Urol Rep. 2005;6:476-81.

Lazarou S, Reyes-Vallejo L, Morgentaler A. Wide Variability in Laboratory Reference Values for Serum Testosterone. J Sex Med. 2006;3:1085-9.

Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol Reprod. 1999;61:1012-6.

Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296:2351-61.

McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. Br J Urol. 2003;91:69-74.

Morgentaler A. The Viagra Myth: The Surprising Impact on Love and Relationships. San Francisco, CA: Jossey-Bass/Wiley, 2003.

Morgentaler A, Crews D. Role of the anterior hypothalamus-preoptic area in the regulation of reproductive behavior in the lizard, Anolis carolinensis: Implantation studies. Horm Behav. 1978;11:61.

Morgentaler A, Bruning CO, III, DeWolf WC. Incidence of occult prostate cancer among men with low total or free serum testosterone. JAMA. 1996;276:1904-6.

Morgentaler A. Male Impotence. Lancet. 1999;354:1713-8.

Morgentaler A. Testosterone and the prostate: is there really a problem? Contemporary Urol. 2006;18:26-33.

Morgentaler A. Testosterone replacement therapy and prostate risks: where’s the beef? Can J Urol. 2006;13:S40-3.

Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treatment Options Oncol. 2006;7:363-9.

Morgentaler A. Testosterone and Prostate Cancer: An Historical Perspective On A Modern Myth. Eur Urol. 2006;50:935-9.

Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen of 4.0 ng/ml or less. Urology. 2006;68:1263-7.

Morgentaler A. Testosterone and sexual function. Med Clin N Am. 2006;90:S32-4.

Morgentaler A. Cultural Biases and Scientific Squabbles: The Challenges to Acceptance of Testosterone Therapy As A Mainstream Medical Treatment. Aging Male. 2007;10:1-2.

Morgentaler A. Guideline for Male Testosterone Therapy: A Clinician’s Perspective. J Clin Endocrinol Metab. 2007;92:416-7.

Morgentaler A. Testosterone Deficiency and Prostate Cancer: Emerging Recognition of an Important and Troubling Relationship. Eur Urol. 2007;52:623-5.

Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin N Am. 2007;34:555-63.

Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, LH and FSH in healthy older men. Metabolism. 1997;46(4):410-3.

Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol. 2005;48:1-4.

Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. 2002;25:55-60.

Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160:105-11.

Rhoden EL, Estrada C, Levine L, Morgentaler A. The value of pituitary magnetic resonance imaging in men with hypogonadism. =J Urol. 2003;170:795-8.

Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol. 2003;170:2348-51.

Rhoden EL, Morgentaler A. Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int J Impot Res. 2004;16:95-7.

Rhoden EL, Morgentaler A. Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy. Int J Impot Res. 2006;18:201-5.Shabsigh R. Testosterone therapy in erectile dysfunction. Aging Male. 2004;7:312-8.

Shores MM, Moceri VM, Gruenwals DA, et al. low testosterone is associated with decreased function and increased mortality risk: a preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc. 2004;52:2077-81.

Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166:1660-5.Tenover JL. Testosterone replacement therapy in older adult men. Int J Androl. 1999 Oct;22(5):300-6.

Traish AM, Toselli P, Jeong SJ, Kim NN. Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for veno-occlusive dysfunction in androgen deficiency. J Androl. 2005;26:242-8.

Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666-72.

The Institute of Medicine Report. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press, 2004.

Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Endocrinol Metab. 2000;85(8):2839-53.

Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med. 2001;111(4): 261-8.

Zvara P, Sioufi R, Schipper HM, Begin LR, Brock GB. Nitric oxide mediated erectile activity is a testosterone dependent event: a rat erection model. Int J Impot Res. 1995;7:209-19.