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Laurance Johnston, Ph.D.

Sponsor: Institute of Spinal Cord Injury, Iceland



1) Melatonin

2) Estrogen

3) Progesterone

4) Testosterone

5) Ghrelin

1)Melatonin: Readily available from vitamin stores and other sources, melatonin is a key hormone produced by the pineal gland. Its production is closely correlated to our sleep-wake cycle and is specifically inhibited by light and stimulated by darkness. The pineal gland converts the amino acid tryptophan into serotonin (a neurotransmitter) and, in turn, melatonin. The melatonin then is released into the bloodstream and cerebrospinal fluid, where it can interact with cells throughout the body.

Through complicated neuroanatomical wiring, photosensitive cells in the retina detect light and send signals to structures that regulate our 24-hour circadian rhythms. These signals then go out of the head to the cervical spinal cord, where are they are routed back to the pineal gland. Hence, cervical, but not lower-level, injuries will compromise the pineal gland and its melatonin production.

Called the sleep hormone, melatonin is used as a sleep-aid for insomniacs, shift workers, and jet-lagged travelers. Because it has been extensively consumed, it is presumably reasonably safe. This is important because animal studies suggest that melatonin is neuroprotective after acute injury. Although we need to be cautious in extrapolating the results of animal studies to humans, its extensive use makes it a better therapeutic candidate for acute injury in humans.

In addition to its hormonal action, melatonin is a powerful antioxidant that protects cells from damaging oxidation. Specifically, it is a highly efficient scavenger of free radicals, which, because they possess an unpaired electron, seek out another electron to achieve a more stable energetic state. Melatonin’s lipophilic structure (i.e., affinity for fat or lipid) allows it to diffuse through the membranes surrounding cells and scavenge free radicals inside the cell.

After the initial mechanical injury in SCI, a complicated physiological chain reaction generates free-radicals, which steal electrons from the lipids in cell membranes. Called lipid peroxidation, this process impairs neuronal and axonal membranes, resulting in further cell death.

Like the frequently administered methylprednisolone, animal studies indicate that melatonin inhibits lipid peroxidation and various injury-aggravating inflammatory processes. Sample studies include:

Dr. Toru Fujimoto and colleagues (Japan) examined melatonin’s neuroprotective effects in rats with experimental SCI. The spinal cords were injured at the T12 level by the pressure of a weight placed on the exposed cord. Melatonin was injected into the body cavity (i.e., intraperitoneally) at 5 minutes, and 1, 2, 3, and 4 hours after injury. Saline was injected into control rats. Because the amount of injected melatonin was much higher than endogenously (i.e., produced from within) generated levels, background levels were not considered experimentally relevant (albeit, see Ates, et al below). Compared to controls, the melatonin-treated rats had less lipid peroxidation, smaller injury-site cavities, and retained more hind-limb function.

Dr. S. F. Erten et al (Turkey) assessed melatonin’s effects in rabbits with spinal-cord ischemia produced by clamping down on blood vessels leading to the cord.  Melatonin was intraperitoneally introduced either 10 minutes before or after clamping. The melatonin-treated rabbits had less lipid peroxidation.

Dr. Jin-bo Liu and associates (China) examined melatonin’s neuroprotective effects in rats with injuries produced by dropping a weight on the exposed spinal cord and dosing them intraperitoneally with melatonin. The investigators concluded that “melatonin can prevent oxidative damage, reduce neurological deficit, and facilitate the recovery from spinal cord injury.”

Drs. Tiziana Genovese and colleagues (Italy) provided further evidence of melatonin’s neuroprotective effects. In their experiments, injury was produced in rats by clipping the exposed spinal cord. Melatonin was administered once before clipping and several times afterwards. The investigators concluded “that melatonin can exert potent anti-inflammatory effects” and enhanced hind-limb functional recovery.

Dr. Suleyman Cayli et al (Turkey) compared the effectiveness of 1) melatonin, 2) the commonly used methylprednisolone, and 3) a combination of the two drugs. After injury was produced in rats by dropping a weight on the exposed cord, the drugs were injected intraperitoneally, and various assessments carried out over time. Compared to controls, improvements were noted in all three treatment groups, including enhanced neuronal conduction, recovery of motor function, decreased injury-promoting lipid peroxidation, and improved injury-site structural integrity. The combination treatment of melatonin and methylprednisolone was best at inhibiting lipid peroxidation.

Earlier, it was implied that the endogenous levels of melatonin produced by the body did not play a significant neuroprotective role after SCI. However, research by Dr. O. Ates and colleagues (Turkey) suggest that physiological background levels may, indeed, be quite important. In addition to looking at the neuroprotective properties of externally administered melatonin, the investigators assessed the effect of removing the rat’s pineal gland and, hence, the body’s melatonin source before injury. Such pinealectomy increased the amount of lipid peroxidation after injury. The investigators concluded: “These findings suggest that reduction in endogenous melatonin after [pinealectomy] makes the rats more vulnerable to trauma…”

These findings actually have considerable relevance to humans. Specifically, for a variety of reasons, including environmental, pineal functioning tends to diminish over time. In adults, melatonin-compromising calcification of the pineal gland is not uncommon, a process in which gritty deposits called brain sand accumulate in the gland. It suggests that individuals with such calcification will have more neurological damage after injury.

In 2012, Dr. M. Ersahin’s investigative team (Turkey) evaluated melatonin’s potential to preserve bladder function in rats experimentally injured at the thoracic T10 level. Results indicated that “melatonin reduces SCI-induced tissue injury and improves bladder functions through its effects on oxidative stress” and nerve growth factor.

In 2012, Dr. S. Park and colleagues (Korea) reported that in rats with SCI produced by contusion “both endogenous and exogenous melatonin contributes to neural recovery and to the prevention of skeletal muscle atrophy, promoting functional recovery after SCI.” The investigators concluded that the study “supports the benefit of endogenous (i.e., produced by the body) and use of exogenous melatonin as a therapeutic intervention for SCI.” Earlier, these investigators investigated the impact of treating injured rats with a combination of melatonin and exercise13). The results indicated that the combined therapy reduces the amount of secondary damage after injury.


2) Estrogen: Although estrogen exerts many physiological effects in both women and men, it is most well known as the female sex hormone. In women, estrogen is primarily produced by the ovaries. It regulates the female estrous or reproductive cycle, and promotes the development of secondary sexual characteristics. Men also produce the hormone but at a much lower level. In men, the hormone is synthesized by the testis and plays a key role in testicular function.

Estrogen derivatives are a key component of many oral contraceptives and also have been used for postmenopausal hormone-replacement therapy. In men, estrogen has been employed to treat prostate cancer. Although estrogen’s reproductive roles receive the most attention, this potent multiactive hormone can influence diverse physiological processes. As such, it theoretically has broad therapeutic potential much beyond its more obvious roles, including as a possible protective agent after neurotrauma.

The SCI neuroprotective possibilities have been extensively studied by Dr. Naren Banik and colleagues at the University of South Carolina using animal models of SCI, as well as cultures of neuronal cells.

Animal Studies: SCI was produced by accessing the thoracic spinal cord of rats through laminectomy and dropping a weight on the exposed cord. Essentially, this is an experimental version of the sort of contusion injury experienced by many individuals with SCI. The rats were then treated intravenously with estrogen 15 minutes and 24 hours after injury, and, for the next five days, with a single daily dose injected into the body cavity. Recovery of locomotor function was followed for six weeks, and the amount of improvement observed compared to similarly injured control rats which received no estrogen.

Locomotion was assessed using the BBB scale, a commonly used animal test which measures recovery of hind-limb function on a scale from 0 (no hind-limb movement) to 21 (normal walking). At the end of the observation period, the average BBB score for the estrogen-treated rats was 13 compared to nine for the controls. Functionally, these statistically significant differences mean that when compared to controls, the estrogen-treated rats were better able to support their body weight, make weight-supported steps, and coordinate hindlimb/forelimb stepping. The investigators concluded that “estrogen treatment significantly increased the locomotor function in the injured animals over the 42-day postinjury period…”

Possible Mechanisms: These investigators and others have devoted much effort trying to understand the specific biological mechanisms by which estrogen mediates neuroprotection. The damage-spreading, pathophysiological cascade after the initial physical insult is extraordinarily complex and is the reason why SCI has been difficult to understand at a molecular level. Given this complexity, as well as estrogen’s increasingly documented, powerful multifaceted role in the body, there are many possible biological systems in which it could target. Some of the possibilities are briefly highlighted below. It is emphasized, however, that these are often complex interlinked and interdependent processes.

1) Calcium Influx: Neuronal conduction depends upon the right balance of calcium ions between the cell inside and outside. Normally, there is a lot of calcium outside of the neuron and relatively little inside.  Injury disrupts the equilibrium, allowing excessive calcium to flow into the cell. This influx initiates a neural-destructive cascade that damages other neurons.  By inhibiting the calcium influx into the cells, estrogen lessens this damaging-perpetuating cascade.

2) Apoptosis: Cells at the injury site die of necrosis, while cells surrounding the site often die from apoptosis, a form of secondary cell death in which a programmed sequence of events leads to cell elimination. As a crude analogy, necrotic cell death is like a quick death from being shot and apoptotic cell death is more like a lingering death from cancer. Because apoptosis is potentially reversible, treatments that turn this process around should help minimize postinjury cell degeneration. By modulating the activity of certain enzymes that promote postinjury apoptosis, estrogen slows down degeneration.

3) Excitotoxicity: Routinely, certain amino acids, like glutamate, are released from a pre-synaptic neuron and flow to a nearby post-synaptic neuron, promulgating the nerve impulse. However, after injury, cells burst, releasing too much glutamate. Through interactions with receptors on neighboring cells, this excessive glutamate will initiate a neurotoxic biochemical cascade. Estrogen protects against this excitotoxicity-caused cell death.

4) Edema: Fluid accumulation at the injury site creates damaging edema swelling. Estrogen-treated rats exhibit less edema.

5) Inflammation: Inflammatory cells infiltrate into the lesion area, which promotes secondary cell death. Estrogen treatment lessens this infiltration.

6) Myelin: The fatty insulation surrounding axons, myelin enables neurons to propagate a signal. SCI often results in axonal demyelination, another process which is attenuated estrogen.

7) Blood Flow: Injury compromises regeneration-promoting blood flow, contributing to secondary cell death. Estrogen promotes the growth of new blood vessels (called angiogenesis), enhancing postinjury blood flow.

8) Antioxidant: After the initial mechanical injury in SCI, free-radicals are generated. Called lipid peroxidation, these free radicals can steal electrons from neighboring cell membranes, resulting in further cell death. A potent antioxidant, estrogen may reduce free-radical-induced oxidative stress.

Given these findings and the fact that women have much higher levels of estrogen than men, it is interesting note that studies suggest that women actually recover more function after neurotrauma.

3) Progesterone: Like estrogen, progesterone also appears to provide neuroprotection. Although called the “pregnancy hormone,” it is also synthesized to a lesser degree by men.

Progesterone is synthesized from cholesterol by the ovaries, adrenal glands, and placenta. In the menstrual cycle, progesterone levels are relatively low before ovulation (i.e., release of a ripe egg from the ovary) and elevated afterwards. Progesterone levels are much higher throughout pregnancy, drop to low levels after birth and during lactation, and recede after menopause. In men, this female-associated hormone is produced by the testes and, paradoxically, is the biochemical precursor to the defining male hormone testosterone.

Progesterone exerts many biological influences throughout the body above and beyond its more well-known effects in reproduction, in part by affecting the expression of other body-regulating hormones. Overall, our optimal functioning is dependent upon a complex, interacting hormonal milieu, whose composition is dependent on many factors, including gender, age, diet, life style, and overall health.

Neurosteroid: With paradigm-expanding implications, progesterone is also produced by and influences the nervous system and, as such, has been termed a “neurosteroid.” Due to this localized synthesis, nervous-tissue progesterone levels are not necessarily a function of plasma levels of the hormone produced by more traditional sources. Neurons and neuronal support cells (called glia) actually have unique progesterone receptors on their outer membrane surface. Like a key fitting in a lock, progesterone’s interactions with these receptors can initiate complex, nervous-system-unique biological responses. Although these responses are only beginning to be understood, they seem to enhance neuronal health and viability.

Many studies suggest that progesterone treatment is neuroprotective after trauma by limiting the loss of neuronal tissue and, as a consequence, preserving function. Because membrane-soluble progesterone can readily diffuse cross the blood-brain-barrier, unlike many drugs, externally administered progesterone has the ability to reach the nervous system. As a result, it has the opportunity to interact with the various progesterone receptors on neuronal cells, shifting the nervous-system environment to potentially a more neuroprotective mode. 

Although we must be careful in extrapolating results to humans, progesterone neuroprotection has been documented in numerous animal models of various neurological disorders, including traumatic brain injury (TBI) and spinal cord dysfunction, such as SCI, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). For example, in animal models of MS, progesterone treatment lessens disease severity, reduces inflammation, and restores the conduction-promoting insulating myelin sheath surrounding neurons (see below). In ALS animal models, the hormone inhibits the degeneration of motor neurons 

TBI: Probably the most research has been directed to TBI, partly because early studies suggested gender differences in recovery after injury. For example, reproductive-cycling female rats with high progesterone levels have less post-injury cerebral edema (swelling) than male rats with inherently low progesterone. Pseudopregnant rats (a pregnancy-like condition), whose progesterone levels are especially high, had little post-injury edema.

Several clinical trials have examined progesterone’s neuroprotective potential in humans. In the first, Emory University investigators (USA) evaluated outcomes in a 100 subjects injured within the previous 11 hours treated with either intravenous progesterone or placebo for three days. Thirty-days post injury, progesterone treatment when compared to controls 1) reduced mortality in the severely injured, and 2) and improved functional outcomes in the moderately injured. 

In a second trial, Chinese researchers randomized 159 patients with severe TBI sustained within the previous eight hours to receive five days of either progesterone or placebo injections intramuscularly. Six months later, progesterone-treated patients showed greater functional improvement and lower mortality.

SCI; Research findings in TBI often, but not always, have relevance to SCI. Although human studies are lacking, extensive SCI-focused animal research builds a strong case in support of progesterone’s neuroprotective potential for SCI. Given the complex physiological cascade that occurs after injury, there are many interacting, biological processes that progesterone could target. For example, studies suggest that post-injury progesterone treatment:

·         Increases levels of growth factors that enhance neuronal survival and axonal regeneration.

·         Restores the expression of enzymes involved in the transport of sodium and potassium ions across the membranes of neurons - a process needed for neural transmission.

·         Protects damaged neurons from cell death and the disintegration of neuron ultrastructure. 

·         Protects neurons from toxic levels of amino-acid neurotransmitters that have been released from nearby damaged cells.

·         Reduces inflammation by decreasing various cells and molecules involved in the inflammatory response.

·         Lessens damage-spreading fluid accumulation or edema.

·         Inhibits oxidation from injury-created free-radicals, which steal electrons from and, as a result, damage neighboring cell membranes.

Remyelination: In addition to the aforementioned, evidence indicates that progesterone promotes the post-injury remyelination of neuronal axons. Myelin is the fatty insulating material enveloping axons, i.e., the fibers that conduct electrical impulses away from the neuron’s cell body to other nerves or muscles.  When axons are demyelinated, channels between the inside and outside of the axon are exposed, in turn, causing disruption in the ionic equilibrium needed for neural transmission. Although most associated with MS, demyelination frequent occurs after SCI. Intact neurons may still traverse the injury site, but because they have lost their insulation, they no longer conduct. In theory, therapies that help restore the myelin sheath should re-establish some function-restoring conduction.

In the spinal cord, myelin is produced by oligodendrocytes, a neuronal support cell which is formed through the differentiation of oligodendrocyte precursor cells. Because oligodendrocytes are extremely sensitive to injury, much-needed remyelination capability is lost. Evidence indicates that progesterone treatment enhances the proliferation of the normally quiescent precursor cells into mature, myelin-producing oligodendrocytes, enhancing the conduction of injury-waylaid neurons.

It is important to note when discussing potential restorative treatments, only a relatively small percentage of intact, functioning neurons are needed to regain significant function. In other words, if progesterone-triggered remyelination can jump-start a few neurons, significant function may accrue.

Hindlimb Functional Recovery: In spite of this promising research, animal studies directed toward recovery of function after SCI are limited and ambiguous in results.  In one study, Dr. Ajith Thomas and colleagues (USA) evaluated the effect of progesterone treatment in rats with SCI produced by contusion, the sort of injury common in humans. After injury, rats received progesterone injected into the body cavity periodically for five days. Compared to controls, six weeks after injury, progesterone-treated animals recovered more function and had more tissue preservation at the injury site.

However, research by Dr, Dominic Fee et al (USA) could not replicate these benefits. Specifically, after an experimental contusion injury, rats were treated with progesterone with several dosing regimens for up to 14 days. Three weeks after injury, no significant improvement in hindlimb function was observed between the progesterone-treated and control animals.

4) Testosterone: Testosterone is primarily produced by the testes in men and, to a lesser degree, 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 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 brain’s 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, it’s like speeding up a manufacturing assembly line.

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; deciliter is one-tenth of liter). 

Only about two percent of the body’s 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 one’s 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, 4) the testicles may have lost their ability to generate testosterone, and 5) medications may suppress production.

Testosterone Replacement Therapy (TRT): Although once the realm of body-building athletes, many have adopted TRT to mitigate the consequences of testosterone diminution from aging or other causes, such as SCI (87). TRT-related benefits potentially include less osteoporosis, type-2 diabetes, cardiovascular disease, erectile dysfunction, depression and anxiety, and Alzheimer’s disease.

TRT requires ongoing monitoring to manage potential side effects. Because testosterone influences many bodily functions, it should be prudently used. 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. 

SCI & Testosterone (88-100) SCI is correlated with many of the problems associated with low testosterone. For example, depending upon the injury, 1) skeletal muscle mass atrophies by 30-60%, and 2) bone loss continues at an enhanced rate for decades (88). 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 potential 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. Several sample studies are summarized below:

1) University of Missouri scientists (USA) have carried out a series of studies evaluating testosterone levels after SCI. In 2006, they examined testosterone levels in 92 men with SCI admitted to inpatient rehabilitation (94). 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 efforts. 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 injuries 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 (92). 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 more 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 (93). 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 those men with incomplete injuries already having residual muscle preservation.

4) Because only a small percentage of total testosterone is biologically active, Dr. Berna Celik and colleagues (Turkey) assessed both total and free testosterone levels in 44 men with SCI recruited from an inpatient rehabilitation unit (91). 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 who had been injured less than a year. In this study, 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 activities of daily living).

5) Dr. William Bauman and colleagues (USA)  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.

Preliminary results were reported in 2011.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.

Neuroprotection: As discussed previously, much evidence suggests that estrogen and progesterone can be neuroprotective after SCI. Both inhibit a variety of neuron-damaging processes that occur after SCI and, by so doing, may limit neuronal tissue loss and preserve function. More limited evidence suggests that testosterone may also exert some neuroprotective role for a variety of nervous-system disorders, including Alzheimer’s disease, ALS (Amyotrophic lateral sclerosis), and perhaps SCI (95).

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 potentially 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 the case of SCI, studies indicate that testosterone inhibits a damage-perpetuating excitotoxicity that occurs soon after injury. Basically, after injury, damaged neurons release an excitatory amino acid called 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.

5) Ghrelin: Ghreline is a 28-amino-acid peptide produced by a various body tissues, especially the cells in the upper portion of the stomach. Increasing before meals and decreasing afterwards, ghrelin is an appetite-enhancing, hunger-stimulating hormone. Although its biology is not well understood, ghrelin interacts with numerous tissues throughout the body, including the central nervous system, suggesting the hormone plays important physiological roles. In the case of the spinal cord, ghrelin complexes with receptors found on the surfaces of neurons and oligodendrocytes,  neuronal support cells which produce the insulating, conduction-promoting myelin surrounding axons.

Recent studies indicate that ghrelin may be neuroprotective after injury by preserving tissue integrity and, as a result, some function (58-60). For example, Dr. Jee Lee and colleagues (South Korea) reported that ghrelin administration improved hind-limb locomotor function in rats experimentally injured by contusion. Their results indicated that this preservation of function was probably due to ghrelin’s ability to inhibit the post-injury death of neurons and oligodendrocytes (a process called apoptosis). This inhibition reduces the size of the injury-induced spinal-cord lesion, preserving axons, as well as the insulating myelin that surrounds them. The investigators concluded that “ghrelin may represent a potential therapeutic agent after acute SCI in humans.”