Previously, I have summarized the relationship of various sex hormones and spinal cord injury. Specifically, I have reviewed the potential of estrogen and progesterone to be neuroprotective after SCI, and most recently provided an overview of testosterone and testosterone replacement therapy (TRT). This update will summarize key studies suggesting that SCI compromises testosterone production, and TRT may ameliorate some of the ensuing consequences and enhance functional recovery after injury.

Review

Briefly, testosterone is primarily produced by the testes in men and, to a lesser degree, the ovaries in women. Testosterone promotes the development of reproductive tissue, sex organs, secondary sexual characteristics, sexual function, muscle mass and strength, and bone density. Because testosterone synthesis is central-nervous-system-driven process, it is not surprising that a major CNS insult like SCI affects testosterone levels.

Low testosterone is associated with osteoporosis, decreased muscle, reduced mental acuity, mood changes, fatigue, less libido, and erectile dysfunction. TRT counters these effects.

SCI

SCI is also associated with many of these problems. For example, after injury, 1) skeletal muscle mass atrophies by 30-60%, and 2) bone loss continues at an enhanced rate for decades. If injury, indeed, compromises testosterone production and that disruption hastens post-injury bone and muscle loss, it becomes an extraordinarily important issue to study, as well as approaches, such as TRT, that may promote function-enhancing hormone levels.  

The results of earlier studies were ambiguous due to confounding factors, such as participant age, time since injury, and injury level or completeness. For example, if one study focused on the acutely injured and another on the chronically injured, results could be different; or if a study didn’t consider such a factor, individual results could offset each other. As investigations better controlled these factors, it has become evident that SCI compromises testosterone levels for many individuals after injury. Key studies are summarized below:

1) University of Missouri scientists have carried out several studies evaluating testosterone levels after SCI. In 2006, they examined testosterone levels in 92 men with SCI admitted to inpatient rehabilitation. Averaging 39 (range 19-92) years old, the injuries were roughly evenly divided between paraplegia and quadriplegia injuries, and complete and incomplete injuries. All had sustained their injuries within the past 15 years. Although most guidelines define low testosterone to be below 300 ng/dl [nanogram is one-billionth of gram; deciliter is one-tenth of liter], the investigators used 240 ng/dl as a cutoff point, a level they called abnormally low.

Overall, 83% had levels below this threshold. Men with more acute injuries (< 4 months) averaged only 160 ng/dl. Given testosterone’s important body-maintenance role, these are shockingly low levels that inevitably compromise recovery. Statistically, the odds for having low testosterone for men with acute versus chronic injuries were 6.7-times greater. Although testosterone differences were noted between paraplegia and quadriplegic, and complete and incomplete injuries, the study was not large enough to demonstrate statistical significance.

2) Reported in 2008, the same group evaluated testosterone levels in 102 men recruited from rehabilitation facilities. Average age was 46 (range 18-82). Testosterone levels averaged 220 ng/dl, with 60% of the subjects having abnormally low hormone levels (i.e., < 240 ng/dl). As before, men with acute injuries were more likely to have low testosterone. Specifically, 69% of individuals in the acute-injury phase (<4 months) had low testosterone compared to only 40% of those in the chronic phase (12+ months).

3) Also in 2008, the investigators reported the results of treating 50 men with TRT recruited within several weeks of injury at an inpatient rehabilitation facility. All had low testosterone levels (averaging 136 ng/dl) and were given monthly, intramuscular injections of the hormone. Because there was no control group, the investigators compared motor recovery of their subjects with the outcomes of 480 non-testosterone-treated men who were included in a national SCI database. This comparison suggested that TRT promoted strength gains in men with incomplete injuries already having residual muscle preservation.

4) Because only a small percentage of total testosterone is biologically active, free testosterone, Turkish scientists assessed both total and free testosterone levels in 44 men with SCI recruited from an inpatient rehabilitation unit (2007). The men averaged 35 (range 16-71) years old, and possessed a spectrum of complete and incomplete injuries at various neurological levels. Twenty-seven and 17 subjects had been injured less and more than one year, respectively. The results indicated that both total and free testosterone was lower in the group whose injuries were more recent. No correlation was found between testosterone levels and function as assessed by the Functional Independence Measure (FIM - a predictor of one’s overall ability to perform daily-living activities).

5) Led by Dr. William Bauman, clinical investigators at the James J. Peters VA Medical Center (NY) and Kessler Institute for Rehabilitation (NJ) have initiated a clinical trial to examine TRT’s potential benefits in 11 men with chronic SCI with low circulating levels of testosterone compared with 11 men with normal levels of the hormone. The subjects who had low levels of testosterone were administered  a testosterone patch daily to return testosterone level to the normal range and, in turn were sequentially evaluated for possible changes in body composition, energy expenditure, and other factors.

The results of this preliminary study were recently reported in Hormones and Metabolic Research. The subjects averaged 43 years old in the treatment group and 35 years old in the control group with average durations of injury for these groups of 12 and 13 years, respectively. In the treatment group, eight subjects had complete injuries and three incomplete injuries. In the control group, nine subjects had complete injuries and two incomplete injuries. After a six-month baseline period, TRT was provided for 12 months, after which there was a six-month washout period in which no hormone was administered.

The findings were that 12 months of TRT significantly improved lean tissue mass (i.e., more muscle) and increased resting energy expenditure (the amount of calories the body burns during rest is also an indicator of an increased total muscle mass). These favorable changes have the potential to improve physical function and general health in men with SCI and low circulating testosterone levels. Future studies will be required to confirm these initial findings and to better define changes in functional performance and other measures of health and well being.

Neuroprotection

As discussed previously, evidence suggests that estrogen and progesterone can be neuroprotective after SCI. Both inhibit neuron-damaging processes that occur after SCI and, by so doing, may preserve function. More limited evidence indicates that testosterone could also be neuroprotective for a variety of nervous-system disorders, including Alzheimer’s disease, ALS, and perhaps SCI.

Testosterone can cross the blood-brain barrier, meaning it can actually get to the target neurons. Furthermore, like a sort of testosterone-specific Velcro, these neurons have receptors that selectively bind the hormone. This binding can trigger a shift towards regenerative physiology. For example, studies have shown that testosterone can increase neuronal differentiation, the outgrowth of neurites (projections like axons and dendrites), cell-body size, formation of synapses (connections) between neurons, and plasticity (processes by which the nervous system returns to normal function).

In SCI’s case, studies indicate that testosterone inhibits damage-perpetuating excitotoxicity that occurs soon after injury. Basically, after injury, damaged neurons release the excitatory amino acid glutamate, which can reach toxic concentrations. Through interactions with receptors on neighboring cells, excessive glutamate will initiate a neurotoxic, biochemical cascade. Apparently, testosterone can protect the spinal cord against such damage.

Conclusion

Although we tend to think of estrogen, progesterone, and testosterone within the context of their more well-known sexual and reproductive roles, these hormones influence our physiology on many levels. In the CNS, they exert numerous subtle, poorly understood effects. As we grow in our understandings, we may be able to use these effects to better steer an injured cord toward recovery.

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

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