As men age, they begin to experience changes in their bodies. Abdominal fat increases and muscle mass decreases. They also experience a distressing decline in their sex drive. At the same time, the risk of serious health conditions such as depression and heart disease rises. While most conventional physicians (and some members of the lay media) dismiss these woes as signs of “natural aging,” there is often an underlying and identifiable cause of these symptoms—the gradual decline of important sex hormones, especially testosterone.

Too often, men who have problems related to a low testosterone level are advised to treat only the symptoms of their conditions (such as taking antidepressant and/or cholesterol-lowering drugs). Fortunately, progressive physicians, along with the Life Extension Foundation, now recognize the connection between hormones and the diseases of aging. Restoration of youthful hormone levels is associated with optimal sexual function, energy, and vitality, while declining hormone levels correlate with many age-related conditions, including high blood pressure, atherosclerosis, diabetes, loss of muscle and bone mass, and fatigue (Shores MM et al 2004).

Factors That Affect Testosterone Levels

Testosterone, which is abundantly produced during puberty, is responsible for the development of secondary sexual characteristics and has profound effects throughout the body. Testosterone receptors are found in virtually all body tissues, so levels of testosterone affect the function of most organ systems. For example, testosterone causes growth of facial and body hair in skin cells, increased fiber size and strength in muscle cells, and maturation of the external genitalia. The effects of testosterone on the central nervous system are also well-known (Okun MS et al 2004). Testosterone governs such behaviors as aggression, risk taking, and territoriality. It is now recognized as an important factor in mitigating depression (King JA et al 2005).

As with all sex hormones, testosterone is part of a cascade that begins with cholesterol, the building block for hormones. Pregnenolone, the “master hormone,” is produced directly from cholesterol. In turn, dehydroepiandrosterone (DHEA; a precursor to testosterone), testosterone (and its metabolites), and estrogen (and its metabolites) are produced from pregnenolone. Both testosterone and estrogen are produced by enzymatic reactions from DHEA. This ubiquitous molecule is the steroid found in highest quantities in humans. Changes in the supply of DHEA (and/or changes in the levels of the enzymes that convert DHEA to the sex hormones) can have powerful effects on sex hormone–dependent systems.

As men age, a number of changes occur that reduce the testosterone level available to the body and that alter the ratio between testosterone and the chief female hormone, estrogen. This condition is now referred to as partial androgen deficiency of aging men (Harman SM 2005).

One of the most important factors that affect testosterone levels of aging men is an enzyme called aromatase, which is found in fat tissue. This enzyme is responsible for converting testosterone into estrogen, thus altering the ratio of estrogen to testosterone (Steiner MS et al 2003). Men who have excessive body fat, especially abdominal fat, are likely to have increased estrogen levels caused by aromatase activity and a dramatically increased estrogen level compared to testosterone. An increased estrogen level has been linked, in turn, to a host of disorders, including decreased insulin sensitivity and blood glucose problems. Some studies suggest that there is an association between a low testosterone level, insulin resistance, an elevated estrogen level, and increased body fat in aging men (Phillips GB 1993).

This relationship between low testosterone and obesity has been described as the hypogonadal/obesity cycle. In this cycle, a low testosterone level leads to an increase in abdominal fat, which leads to increased aromatase activity, which leads to further conversion of testosterone to estradiol, which further reduces testosterone and increases the tendency toward abdominal fat (Cohen PG 1999).

The effect of sex hormones on tissues is also affected by the level of sex hormone–binding globulin (SHBG). Sex hormones circulate in the bloodstream in very small quantities as free molecules. The bulk of sex hormones are bound to SHBG, which is a specialized carrier protein (Nankin HR et al 1986). Hormones bound to carrier molecules are inactive, so the amount of SHBG has an important impact on the degree to which tissues respond to sex hormone levels (Misao R et al 1999; Zmuda JM et al 1993; Dambe JE et al 1983; Van Look PF et al 1981). Nutritional status and the levels of other hormones are among the factors that determine levels of SHBG.

Aging men who have an androgen deficiency experience both an increase in aromatase activity and an elevation in SHBG production. The net result is to increase the ratio of estrogen to testosterone and lower the total testosterone level (Killinger DW et al 1987; Kley HK et al 1980a,b). Finally, it is important that aging men also strive for optimal liver function. The liver is responsible for removing excess estrogen and SHBG, so any compromise in liver function (such as that caused by heavy alcohol consumption, for example) can exacerbate hormonal imbalances.

Effects of Age-Related Decline in Testosterone Levels

The exact causes of the age-related reduction in testosterone levels is not known; it is probably the result of a combination of factors, including increased body fat (and therefore increased aromatase activity), oxidative damage to tissues responsible for the production of testosterone, and declining levels of precursor molecules such as DHEA. The results of the decline, however, are strikingly apparent.

Nervous system effects. Low testosterone levels have been associated with depression and other psychological disorders (Barrett-Connor E et al 1999b; Rabkin JG et al 1999; Schweiger U et al 1999; Seidman SN et al 1999; Moger WH 1980). In addition, many conventional antidepressants suppress libido. Some experts recommend that patients whose reduced libido is caused by taking antidepressants undergo testing to have their testosterone levels checked—and that they get supplemental treatment if necessary. Others suggest that testosterone therapy might reduce the need for the antidepressants themselves (Goldstat R et al 2003; Morley JE 2003). Feelings of well-being are often reported with testosterone treatment (Carnahan RM et al 2004; Dunning TL et al 2004; Orengo CA et al 2004; Wright JV et al 1999).

Cognition and alertness are also governed in part by testosterone’s effects on the central nervous system (Cherrier MM et al 2004; Cherrier MM et al 2001; Janowsky JS et al 2000). Low testosterone levels have been shown to correlate with lower scores on various psychometric tests (Moffat SD et al 2002; Barrett-Connor E et al 1999a; Janowsky JS et al 1994). Similar effects have been reported in men taking androgen-deprivation therapy for prostate cancer (Salminen EK et al 2004). Testosterone’s ability to protect nerve cells against a variety of toxins, including oxidative stress (Ahlbom E et al 2001) and the Alzheimer’s protein beta-amyloid (Zhang Y et al 2004; Hammond J et al 2001), may explain the low testosterone levels found in men who have neurodegenerative diseases (Hogervorst E et al 2004; Okun MS et al 2004; Ready RE et al 2004).

Sexual enjoyment and function. Falling levels of free testosterone diminish sexual desire, as well as pleasure and performance in sexual activity. There is evidence that, in men with low free testosterone levels, replacement therapy can improve sexual function (Tenover JL 1998; Anderson RA et al 1992; Ahmed SR et al 1988; Davidson JM et al 1982).

Cardiovascular disease and metabolic syndrome. There is a clear relationship between low levels of testosterone and increased incidence of cardiovascular disease, particularly as testosterone level relates to metabolic syndrome (Dobrzycki S et al 2003; Hak AE et al 2002; Zhao SP et al 1998; Jeppesen LL et al 1996). Metabolic syndrome is the combination of abdominal obesity, high blood pressure, insulin resistance, and lipid disorders in the same person. This condition is associated with a high risk of cardiovascular disease. Studies have shown that testosterone administration (500 milligrams [mg] of intramuscular injections) in middle-aged, obese men was able to increase insulin sensitivity (Marin P et al 1992a). These results were confirmed in another study in which testosterone treatment led to reduced insulin resistance (Marin P et al 1992b). Later studies also showed that testosterone administration is helpful in the context of metabolic syndrome (Bhasin S 2003; Boyanov MA et al 2003).

The musculoskeletal system. Bone integrity depends upon a balance between bone formation and bone resorption, which are controlled by multiple factors including estrogen and testosterone (Rucker D et al 2004; Tok EC et al 2004; Valimaki VV et al 2004). One clinical trial has demonstrated that testosterone increases bone mineral density in elderly men (van den Beld AW et al 2000). Testosterone supplementation also has a positive effect on muscle metabolism and strength (Herbst KL et al 2004). The effect is undiminished with age, although older men have a greater incidence of adverse effects.

The Importance of Hormone Testing

When testosterone levels are measured, it is critical to determine the levels of both free and total testosterone to understand the cause of any observed symptoms of deficiency or excess (Pardridge WM 1986).

The Life Extension Foundation believes that a comprehensive battery of tests, along with a careful physical examination, is helpful in detecting hormonal imbalances in aging men. If testing is conducted, it is important to remember that blood levels of both free and total testosterone vary widely among individuals, making it difficult to establish a general threshold for treatment. However, levels are quite consistent within individuals, so it is helpful for men to have multiple tests over time to determine trends and individual thresholds for treatment.

It is also important to note that so-called normal levels of testosterone for older men reflect averages in the current population. The Life Extension Foundation believes that most aging men would prefer not to accept the loss of youthful vigor as normal. Instead, we suggest that a more valid optimal range for all men would be in the upper one-third of the range for men aged 21 to 49 years, and that any supplementation should aim to restore hormone levels to that range.

Finally, during the initial testing, it is imperative to also test estrogen levels. Many of the unwanted effects of male hormone imbalance are actually caused by an elevated estrogen level relative to testosterone level (the estrogen/testosterone ratio).

Using Hormone Replacement Wisely

If a man chooses to pursue hormone testing with the intention of using testosterone supplementation (available orally or as an injection, implant, or skin patch), he should keep several facts and precautions in mind (Rhoden EL et al 2004; Schaeffer EM et al 2004):

• The patterns and trends over time of multiple hormone levels (such as free testosterone, total testosterone, and estrogen) determine the specific hormone replacements required.
• It is not safe to use large amounts of testosterone in any form.
• Hormone replacement should not be initiated without comprehensive testing.
• Because of the risk of worsening prostate cancer, careful screening for prostate cancer, including a digital rectal examination and prostate specific antigen (PSA) screening, must be done before starting any hormone replacement program.
• Certain conditions are contraindications to hormone replacement (Ebert T et al 2005). Prostate cancer, in particular, can be made worse by increasing available testosterone.
• A man who is contemplating taking hormone replacement, whether through a prescription or through supplements, should work closely with a qualified physician to plan a rationale approach to treatment and continued monitoring and screening.

Testosterone Therapies

Synthetic anabolic steroids. Synthetic anabolid steroids sold in the form of patches, creams, pellets, and tablets are chemically different from the testosterone made by the body and do not accomplish the same effect as natural testosterone. These drugs are aimed primarily at the musculoskeletal system and are known to have myriad toxic side effects, including causing serious heart and kidney complications. They are sometimes abused by athletes and bodybuilders who want to build muscle mass. A few of the synthetic testosterone drugs that men should avoid using on a long-term basis are methyltestosterone, danazol, oxandrolone, testosterone propionate, cyclopentanepropionate, and enanthate.

Testosterone patches, creams, pellets and tablets. Scientists learned decades ago how to make the identical testosterone that a man’s body produces. However, because natural testosterone could not be patented, drug companies developed all kinds of synthetic testosterone analogues. Currently available recommended natural testosterone drugs include testosterone transdermal patches and testosterone creams, pellets, and sublingual tablets.

Both synthetic testosterone and natural testosterone require a prescription. A physician should prescribe testosterone only after a man’s blood tests have verified that he has a testosterone deficiency.

Alternative physicians usually prescribe testosterone creams (available at compounding pharmacies). Conventional physicians are more likely to prescribe testosterone patches. All forms of natural testosterone are the same and all will markedly increase free testosterone in the blood and saliva.

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