MALE HORMONE RESTORATION:
OPTIMIZING TESTOSTERONE LEVELS IN MEN

Testosterone is the primary male sex hormone, responsible for male sexual development and critical in maintaining multiple body functions. It is vital in sustaining proper erectile function and libido and plays a big part in building muscles and burning fat as well as supporting normal energy levels, mood, immune function and bone density.

Testosterone levels decline with age, beginning to diminish as early as the mid-thirties. By the age of 80, a man’s testosterone level is often only 20% of what it was in his youth. This gradual decline can result in a number of disturbing symptoms, including loss of stamina and lean muscle mass, reduced libido, anxiety, depression, obesity and cognitive decline. This testosterone deficiency syndrome, also known as andropause, is the male equivalent of female menopause. Because the drop in testosterone is so gradual, the symptoms of andropause appear over a longer period of time as compared to female menopause and are often ignored for awhile or are attributed to “getting older”. There is good news for men, however, in that many of these symptoms are reversible by restoring healthy testosterone levels. This can be done in a variety of ways, and now millions of men are now using testosterone building supplements and even testosterone itself for this reason.

Recognition of an Increasingly Prevalent Problem
Some physicians estimate that currently more than 5 million men in the United States may suffer from the effects of low testosterone levels. This number is only going to increase in the future, as the number of men in the United States between the ages of 45 and 84 is expected to increase to 62 million by the year 2020. (1) According to pharmaceutical industry estimates, a total of 2.3 million prescriptions for testosterone were written in 2005, a 50% increase from 2001. (2) Perhaps physicians are increasingly recognizing the consequences of low testosterone levels in aging males.

Medical studies suggest an association of low testosterone with increased morbidity and mortality. In a recent study by Khaw et al., men with lower testosterone levels were more likely to die due to cardiovascular disease and all causes compared to men with higher levels. The authors concluded that low testosterone may be a predictive marker for those at high risk of cardiovascular disease. (3) Another review from the Baylor College of Medicine has reported that there is a higher prevalence of depression, coronary heart disease, osteoporosis, fracture rates, frailty and even dementia with low testosterone states. (4) You might now be asking yourself these questions: Why hasn’t my doctor discussed these risks with me and why haven’t I been tested for low testosterone levels? Why am I just now hearing about this?

Testosterone Supplementation: A Shady Past
A major reason is that the conventional medical community has been slow to warm to the idea and in fact wrongly believes that restoring youthful levels of testosterone is dangerous and unwarranted. Back in the mid 1900’s, some drug companies sold a synthetic and chemically altered testosterone called methyltestosterone. They pawned this chemical off as real testosterone, even though it does not naturally exist in the human body. After several years on the market, some men taking this particular chemical developed liver cancer. “Testosterone therapy” was then declared to be dangerous and research about testosterone fell by the wayside.

When bioidentical Testosterone became more widely available in the 1980s, its reputation did not improve. Beginning in the late 1980’s, overambitious and unscrupulous professional athletes began taking illegal anabolic steroids to gain an unfair competitive edge. While testosterone is a member of the group of compounds known as “anabolic steroids” it is different and less potent than the illegal synthetic compounds that have been taken in excessive doses and abused. Unfortunately, this abuse has wrongly clouded the important health benefits that are gained with the accepted medical practice of prescribing testosterone therapy for the decline associated with aging and other diseases. In response to the sports abuse issue, federal law has made Testosterone a controlled substance just like narcotics and amphetamines. Illegal use penalties can be severe for any doctor who improperly prescribes anabolic steroids. No wonder some doctors are reluctant to prescribe it. Testosterone got another poke in the eye recently when the American professional cyclist Floyd Landis was stripped of his 2006 Tour de France title after testing positive for exogenously administered testoste rone.

Evolving Opinions on Testosterone Replacement
In November 2002, the Institute of Medicine declared that "existing scientific evidence does not justify claims that testosterone treatments can relieve or prevent certain age-related problems in men." Most Age Management physicians strongly disagree with that statement. There are hundreds of studies in the medical literature showing the health benefits and safety of testosterone therapy.

In 2007, Drs. Miner and Seftel published a review of the medical literature on testosterone since the 2002 Institute of Medicine Report. (5) The summary of their article states: “Recent studies have demonstrated that hypogonadism (low testosterone) in men may be more prevalent than previously thought, is strongly associated with metabolic syndrome, and may be a risk factor for type 2 diabetes and cardiovascular disease. Clinical studies have shown that testosterone replacement therapy improves metabolic syndrome indicators and cardiovascular risk factors. Maintaining testosterone concentrations in the normal range has been shown to contribute to bone health, lean muscle mass, and physical and sexual function, suggesting that testosterone replacement therapy may help to prevent frailty in older men. Based on current knowledge, testosterone replacement therapy is unlikely to pose major health risks in patients without prostate cancer and may offer substantial health benefits.” Perhaps conventional medicine is warming to an idea whose time has come.

Testosterone and Cardiovascular Health
Let’s take a closer look at what the medical literature says about the specific benefits of testosterone restoration. Many studies have shown an association between low testosterone levels and a higher prevalence of coronary artery disease (6,7,8) and aortic atherosclerosis. (8) Lower testosterone levels are also associated with reduced pumping ability of the heart. (7)

Recent studies suggest that Testosterone replacement may be associated with clinical improvement of the symptoms of coronary artery disease. A placebo-controlled crossover study in men with ischemic heart disease and low testosterone levels reported that exercise time and the time to development of ischemic changes on a treadmill test was increased with testosterone replacement therapy. (9) Another placebo-controlled study found that 12 weeks of oral testosterone replacement therapy improved the ability of the brachial artery to dilate in men with coronary artery disease. (10) These and other medical studies provide mounting evidence of the clinical benefits of testosterone replacement therapy in men with coronary artery disease.

Testosterone and Body Composition
With the obesity epidemic raging and its tremendous impact on the overall health of our nation’s population, I’m particularly interested in the role Testosterone plays in body composition. Testosterone appears to affect fat cell metabolism and fat loss in several ways: It appears to inhibit fat storage by inhibiting a key enzyme, lipoprotein lipase, which is necessary for the uptake of fat into the fat cell. When fat cells are exposed to testosterone in a test tube, the activity of lipoprotein lipase is dramatically reduced. Additionally, testosterone stimulates fat burning by increasing the number of certain receptors on the fat cell membrane that are involved in the release of stored fat from the fat cell. (11)

Does the administration of testosterone to testosterone deficient adults result in favorable body composition changes? In a landmark study out of Sweden in 1991, researchers gave a group of overweight older men supplemental testosterone for six weeks (12). When it was measured after 6 weeks, lipoprotein lipase activity in abdominal fat tissue was dramatically reduced. Waist and hip circumference also dropped in 9 of the 11 men.

In the past several years, numerous placebo controlled trials have demonstrated both significant increases in lean body mass and decreases in fat mass after varying courses of testosterone supplementation in older men. (13) In these studies, the greatest favorable changes in body composition were seen in those study participants who had low baseline testosterone levels and received testosterone therapy for a period in excess of 12 months.

Testosterone and the Prostate
A common misconception among physician is that testosterone administration adversely affects the normal prostate. This idea is not supported by the medical literature. In 2002, a study was published that examined a group of men with low or low-normal testosterone levels. (14) The researchers looked at multiple parameters, including prostate volume, PSA and lower urinary tract symptoms. Of the 207 men studied, 187 responded favorably to testosterone treatment. These 187 all showed improvement in almost every parameter measured: their prostate glands all decreased in size, their PSA numbers went lower, and frequency, urgency, dribbling, and getting up at night all improved. Far from causing trouble, this study seemed to indicate that testosterone is actually beneficial for the prostate gland in the vast majority of cases.

In a separate recent study that looked at a similar group of men, the authors observed that "No treatment-related change was observed in prostate histology, tissue biomarkers, gene expression, or cancer incidence or severity. Treatment-related changes in prostate volume, serum PSA, voiding symptoms, and urinary flow were slight" (15).

What about testosterone and prostate cancer? Does testosterone therapy cause prostate cancer? The answer clearly appears to be no. In a landmark review article published in 2004 in the New England Journal of Medicine, the authors report “there appears to be to be no compelling evidence at present to suggest that men with higher testosterone levels are at a greater risk of prostate cancer or that treating men who have hypogonadism (low testosterone) increases this risk”. (16) However, since testosterone stimulates cell growth, it is possible that it can accelerate the growth of an existing prostate cancer. Cancer screening tests such as a PSA are necessary prior to replacement therapy. Testosterone replacement therapy is contraindicated in men with known prostate cancer.

Testosterone and Depression
Depression is a leading cause of disability worldwide, affecting 2% to 5% of the population. In a recent study of 3987 older men in Australia, those with depression had significantly lower testosterone concentrations than men without depression. (17) The authors suggested that older men with depression may benefit from systematic screening of testosterone levels and testosterone supplementation where appropriate. Other studies have shown an improvement in depression scores in those patients with depression unresponsive to conventional treatments who have undertaken a trial of testosterone therapy. (18,19) Further research in this area is ongoing.

Testosterone Improves Cognitive Abilities
Testosterone supplementation clearly seems to be beneficial for proper male mental and verbal function. Several studies have shown that decreased serum testosterone levels appear to adversely affect verbal memory in normal young men. Short term testosterone administration exerts a beneficial effect on spatial and verbal memory and enhances cognitive function in healthy older men. (20, 21, 22, 23)

Side Effects of Excess Testosterone
The most common immediate adverse side effects associated with testosterone replacement (occurring in no more than 6% of users) include: acne, oily skin, headache, blood pressure increase, and aggressiveness or irritability. Other important side effects that your doctor should be vigilant about include worsening of sleep apnea, breast enlargement, testicular atrophy, excess red blood cell count (erythrocytosis), and insomnia. With careful monitoring of clinical and laboratory parameters, and keeping testosterone levels within the optimal physiologic range, these side effects can be avoided or minimized.

Management of Low Testosterone Levels
Optimizing testosterone levels in men requires a multi-faceted approach that includes proper lifestyle, nutrition, nutritional supplements, dietary restrictions and exercise recommendations as well as testosterone supplementation when indicated. Initially, a medical history and physical examination should be performed, along with a blood testing panel which includes not only testosterone levels, but also other important parameters such as fasting glucose, PSA, estradiol and CBC. It is important to work closely with a knowledgeable physician who is readily accessible and who can monitor adverse side effects and adjust treatment as needed. Careful, thoughtful optimization of testosterone levels with a comprehensive evaluation and treatment plan can result in dramatic improvements of one’s overall health and well-being.

References:

(1) U.S. Census Bureau, 2004, “ U.S. Interim Projections by Age, Sex, Race, and Hispanic Origin”
(2) Extent and nature of testosterone use [news release]. Fairfield, Conn: IMS Health; September 2006.
(3) Khaw K., et al. “Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men.”Circulation. 2007;116:2694-2701.
(4) Salazar, J., “Risks of Testosterone Replacement Therapy in Ageing Men.” Summary Expert Opinion on Drug Safety. November 2004, Vol. 3, No. 6, Pages 599-606
(5) Miner M. and Seftel A., Testosterone and Ageing: What Have We Learned Since the Institute of Medicine Report and What Lies Ahead? Int J Clin Pract. 2007;61(4); 622-632
(6) Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS. Testosterone and atherosclerosis in aging men: purported association and clinical implications. Am J Cardiovasc Drugs 2005; 5: 141-54
(7) Dobrzycki S et al. "An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males." J Med Invest 2003; 50(3-4):162-169.
(8) Hak et al., “Low Levels of Endogenous Androgens Increase the Risk of Atherosclerosis in Elderly Men: The Rotterdam Study” J Clin Endocrinol. Metab., Aug 2002; 87: 3632 - 3639
(9) Malkin CJ, Pugh PJ, Morris PD et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart 2004; 90: 871-6
(10) Kang SM, Jang Y, Kim JY et al. Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. Am J Cardiol 2002; 89: 862-4
(11) De Pergola, G.,The adipose tissue metabolism: role of testosterone and dehydroepiandrosterone. International Journal of Obesity and Related Metabolic Disorders, (2000) 24, S59-63
(12) Rebuffe-Scrive, M., Marin, P., & Bjorntorp, P. (1991). Effect of testosterone on abdominal adipose tissue in men. International Journal of Obesity, 15, 791-795
(13) Allen et al., “Body Composition, Metabolic Syndrome and Testosterone in Aging Men” Int J Impot Res. 2007;19(5):448-457
(14) Perchersky AV et al. "Androgen administration in middle-aged and aging men: effects of oral testosterone undecanoate on di-hydrotestosterone, oestradiol, and prostate volume." International J Andrology 2002; 25(2): 119
(15) Marks, Leonard S., Effect of Testosterone Replacement Therapy on Prostate Tissue in Men With Late-Onset Hypogonadism A Randomized Controlled Trial. JAMA. 2006;296:2351-2361.
(16) Rhoden and Morgentaler, “Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring” NEJM Volume 350:482-492 Jan 29, 2004.
(17) Almeida et al., “Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men.” Arch Gen Psychiatry. 2008 Mar;65(3):283-9.
(18) Pope et al., Testosterone Gel Supplementation for Men with Refractory Depression: A Randomized, Placebo-Controlled Trial. Am J Psychiatry. 2003 Jan;160(1): 105-111
(19) Seidman & Rabkin., “Testosterone Replacement Therapy for Hypogonadal Men with SSRI-Refractory Depression” J Affect Disord. 1998 Mar;48(2-3):157-161.
(20) Cherrier MM et al. "Testosterone supplementation improves spatial and verbal memory in healthy older men." Neurology 2001; 57(1): 80-88.
(21) Cherrier MM et al. "Cognitive effects of short-term manipulation of serum sex steroids in healthy young men." J Clin Endocrinol Metab 2002; 87(7): 3,090-3,096.
(22) 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(4): 568-576.
(23) Cherrier MM et al. "Relationship between testosterone supplementation and insulin-like growth factor-I levels and cognition in healthy older men." Psychoneuroendocrinology 2004; 29(1): 65-82.

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