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Laurance Johnston, Ph.D.

Elsewhere, Iíve discussed the potential of two female-associated hormones, estrogen and progesterone, to be neuroprotective after spinal cord injury. Both inhibit a variety of neuron-damaging processes that occur after SCI and, by so doing, may limit neuronal tissue loss and preserve function. This installment will specifically provide an overview of testosterone and testosterone replacement therapy (TRT).

Although viewed as the virilizing male hormone, women also produce small amounts of testosterone. The hormone is primarily produced by the testes in men and the ovaries and placenta in women. Small amounts are also produced by the adrenal glands. In men, testosterone promotes 1) the development of reproductive tissue, sex organs, and secondary sexual characteristics such as body hair and voice deepening (i.e., androgenic role); and 2) sexual function, growth of muscle mass and strength, and bone density (i.e., anabolic influence). The second benefit also makes testosterone important in women.

Testosterone Production

Testosterone is synthesized from cholesterol, which is an essential biochemical building block for many hormones and nervous-system molecules. Its production is regulated by the hypothalamic-pituitary-testicular axis, a tongue-tying description for a regulatory, feedback loop used by our bodies to attain hormonal balance.

Briefly, the hypothalamus, a region of the brain located above the brain stem, regulates the release of key hormones by the nearby pituitary gland, which then stimulates testicular cells to produce testosterone. However, as testicular production increases, the elevated testosterone levels start shutting off the brainís release of testosterone-stimulating molecules. As a result, testosterone output decreases (figure). Because testosterone synthesis is central-nervous-system-driven process, a major CNS disruption like SCI can affect testosterone levels.

Carried via the bloodstream, the testicular-synthesized testosterone (or its derivatives) reaches the target tissue, such as muscle, bone, sex organs, kidney, liver, and brain. It is then transported into the cells and interacts with the DNA of specific genes. This interaction cranks-up gene expression and, in turn, the tissue products resulting from that expression - e.g., more muscle, etc. As a simple analogy, itís like speeding up a manufacturing assembly line.

Testosterone Levels

Normal testosterone blood levels range from about 300-1,000 and 25-90 nanograms per deciliter in men and women, respectively (nanogram is one-billionth of gram (~28 grams/ounce); deciliter is one-tenth of liter).  

Only about two percent of the bodyís testosterone is biologically active free testosterone. The remaining testosterone is either 1) bound to albumin, a carrier protein in the blood plasma (yet still bioavailable), or 2) complexed with sex hormone binding globulin (SHBG) (no longer bioavailable). To give a better idea of oneís true testosterone status, laboratory assessments should measure both total and free testosterone.

Low testosterone levels are referred to as hypogonadism, a condition associated with osteoporosis (loss of bone density), decreased lean body mass (i.e., more fat), less strength, reduced mental acuity and focus, mood changes, fatigue, less sexual desire, and erectile dysfunction. As men age, testosterone levels decline, a process called andropause after middle age.

In addition to age, various factors contribute to low testosterone levels. For example, 1) excessive amounts of the hormone can be converted into estrogen, 2) as men age or become sick, more testosterone is taken out of commission by binding proteins, 3) the pituitary and hypothalamus may not release sufficient hormones to adequately stimulate testicular testosterone production, and 4) the testicles may have lost their ability to generate testosterone.

Testosterone also can be compromised by various medications. For example, an elderly relative of mine was given a drug to treat his prostate cancer. The drug works by knocking off testicular testosterone production thereby depriving hormone-dependent cancers of the testosterone they need to grow. Unfortunately, eliminating a key body-strengthening hormone is not innocuous. In my relativeís case, his six-foot, three-inch frame drastically shriveled due to osteoporosis and muscle wasting, making me wonder, which was worse: the cancer or the treatment.

Testosterone Replacement Therapy

Although once the realm of body-building athletes, many have adopted TRT to mitigate the consequences of testosterone diminution from aging or other causes. TRT-related benefits potentially include less osteoporosis, type-2 diabetes, cardiovascular disease, erectile dysfunction, depression and anxiety, and Alzheimerís disease. Although these rejuvenating benefits sound appealing, one should approach TRT carefully, weighing the pros and cons relative to oneís unique situation with guidance of a physician well experienced in the issues involved.

TRT requires ongoing monitoring to manage potential side effects. Because testosterone influences many bodily functions, it should be prudently used. When it comes to TRT, keep in mind the old margarine commercial: ďItís not nice to fool Mother Nature.Ē Modern medicine is replete with many examples of drug-related side effects emerging years after treatment.

A foremost consideration is that TRT should be viewed as a long-term commitment to not only the therapy but various medical assessments that should be carried out on an ongoing basis. TRT will shut down testicular testosterone production. By taking testosterone, you will disrupt the aforementioned hypothalamic-pituitary-testicular feedback loop and turn off whatever limited synthesis you had before treatment.  As a result, if you have to discontinue TRT for any reason, your body will be generating little testosterone, and your physical and mental state will reflect this paucity. The body probably will eventually recover to baseline levels, but it may take a while. 

As summarized in the table bar, TRT has used a variety of formulations.

Oral Agents are quickly absorbed and metabolized by the liver and may be toxic to this organ.
Intramuscular Injections are commonly used. Weekly/biweekly injections are often self-administered. This regimen produces a yo-yo effect in which testosterone levels peak after injection and fade until the next injection. Long-lasting formulations being developed may minimize the effect. (Cheapest option)
Transdermal Gels are applied daily to skin areas that minimize accidental transfer to others, i.e. you donít want to get testosterone on your child after a hug. Daily use prevents yo-yo effect.
Transdermal Patches: Skin irritation is possible, and patch visibility may be of concern.
Pellets: Longer-lasting, grain-of-rice-size pellets are implanted underneath the skin.
Sublingual/Buccal dissolvable tablets are placed under the tongue (sublingual) or by the gums (buccal). Because little is swallowed, liver toxicity is minimized. It requires to be used 2-3 times a day, which may be impractical for many.

Potential Side Effects

TRT should be viewed as a double-edged sword, in which clear benefits must be balanced against potential side effects, including the following:

Prostate Health: Testosterone stimulates the growth of prostate cancer cells. Evidence suggests that TRT does not cause cancer but can aggravate it if present. With respect to the benign prostate enlargement commonly faced by many aging men, TRT doesnít aggravate the condition.

 Blood Viscosity: TRT stimulates red-blood-cell production, which may make the blood overly viscous. This can compromise blood circulation, predisposing one to high blood pressure and more strokes and heart attacks. The condition, which occurs in a small proportion of men, can be readily resolved by periodic blood donation.

Breast Enlargement: If too much testosterone is converted to estrogen, men may develop enlarged breasts. This also occurs in a small proportion of men and can be treated with estrogen blockers.

Low Sperm: High testosterone levels can inhibit sperm production. Men who want children often have to discontinue TRT.

Testicular Atrophy: Long-term TRT can cause the testicles to shrink, a reversible and treatable condition.

Moodiness: High-dose testosterone users (i.e., like some bodybuilders) may experience manic episodes.

Acne and Baldness: Because testosterone derivatives stimulate skin sebaceous gland secretions, acne can develop. Men already losing hair may lose more hair.


Part 2 will look at SCIís disruption of testosterone production and how that disruption may affect post-injury health and wellness. Evidence suggests that treatment with testosterone, an agent known to increase muscle and bone mass, may lessen functional loss after injury.

Resource: A good starting-point reference is Testosterone: A Manís Guide by Nelson Vergel, available at www.testosteronewisdom.com.

Adapted from article appearing in August 2011 Paraplegia News (For subscriptions, call 602-224-0500) or go to www.pn-magazine.com