Proper hormonal signaling is essential for the physiological adaptations to exercise training. Dependent on the magnitude of the training stimulus, often defined by acute program variables such as load, volume, duration, modality, and rest, hormones elicit specific training adaptations. Testosterone, cortisol, dehydroepiandrosterone (DHEA), GH, insulin-like growth factor 1 (IGF-1), sex-hormone binding globulin, and luteinizing hormone (LH) are among the key hormones demonstrated to be critical to athletes.
Testosterone is required for promoting protein synthesis, red blood cell production, and glycogen replenishment and for reducing protein breakdown. Decreased testosterone levels accompanied by decreased performance, energy, or strength observed during a training season may indicate that that training volume is too high. In this case, an athlete may benefit from temporarily reducing training volume. Cortisol works antagonistically to testosterone, inhibiting protein synthesis by interfering with testosterone's binding to its androgen receptor and by blocking anabolic signaling through testosterone-independent mechanisms. When chronically elevated, cortisol is catabolic and immunosuppressive leading to circumstances that make it more difficult for an athlete to build/maintain muscle mass and recover from training.
In addition to monitoring testosterone and cortisol separately, monitoring their relative levels (T:C ratio) during a training season may provide a relative indication of anabolic-catabolic balance, especially in male athletes (133). T:C ratio is considered more sensitive to training stresses than either measure alone. A prolonged decrease in T:C is associated with detriments to performance through increased proteolysis (muscle protein breakdown) and decreased protein synthesis. A 30% decrease in T:C has been suggested as an indicator of insufficient recovery (8,138), whereas a value of 0.35 × 10−3 has been considered to be the threshold of overtraining (138). Poor performance outcomes and suboptimal training adaptations have been reported in both soccer athletes (70) and tactical athletes (26) with a low T:C ratio.
As other hormones moderate physiological adaptations to training, especially in female athletes, monitoring other hormones, such as SHBG or DHEA-S in relation to cortisol may provide additional insights into the anabolic to catabolic balance in both male and female athletes. Dehydroepiandrosterone is a precursor hormone to both estrogen and testosterone. In addition to affecting body composition (56) in athletes, changes in DHEA in relation to cortisol have been reported to be a useful marker of susceptibility to overtraining in the female athlete (16,42). Similarly, SHBG is a useful indicator of training status and performance (strength and rate of force development) (40). SHBG transports hormones such as testosterone in the body and increases in response to exercise training in both male and female athletes. Increased SHBG is believed to protect sex hormones from being degraded by protecting the biologically active free sex hormones in circulation. Increased SHBG and decreased testosterone may indicate insufficient recovery (53). Low SHBG may merely represent an individual's chronic diet (1); diets high in fat and protein may be associated with low levels of SHBG and high levels of sex hormones (1) and may be considered a sign of suboptimal capacity to adapt to training (133).
Other key hormones inform us about training adaptations. These include GH, IGF-1, and LH. Growth hormone stimulates anabolism by promoting muscle protein synthesis and inhibiting protein breakdown. Growth hormone concentrations have been correlated to exercise volume and intensity. Growth hormone increases levels of circulating IGF-I, both of which hormones are involved in muscle mass regulation, making IGF-1 and GH together potentially useful biomarkers. Luteinizing hormone is associated with reproductive function in men and women. Luteinizing hormone may be another useful marker to detect overtraining or insufficient energy intake.
After muscle-damaging exercise, the enzyme CK leaks from the muscle into the circulation (69,86). It is typical for athletes to have elevated CK during training, with reference ranges of 82–1,083 U·L−1 in male and 47–513 U·L−1 in female athletes suggested as athletic norms (86). Monitoring CK levels during training in comparison with baseline levels may help athletes to monitor muscle status. Creatine kinase levels peak approximately 24 hours after damaging exercise such as heavy strength training, but may remain elevated up to 7 days after exercise. Chronically elevated CK may indicate insufficient recovery. Because other components of muscle such as myoglobin may leak into circulation during muscle damage (peak 1–3 hours after exercise), and urea nitrogen can indicate overall protein synthesis vs. breakdown (59), using all 3 markers to determine an athlete's muscle status during training and recovery will be useful to athletes, coaches, and clinicians.
Iron is an important mineral in oxygen transport and oxidative phosphorylation which are fundamental physiological processes required for aerobic metabolism and cardiovascular endurance performance (60). Endurance athletes, especially females (113), are particularly susceptible to iron deficiency because of one or a combination of the following factors: menstrual bleeding, poor dietary intake, exercise-related gastrointestinal tract bleeding, hematuria, sweating, poor intestinal iron absorption due to subclinical exercise-induced inflammation (97), and erythrocyte destruction through repeated foot striking (98), elevated intramuscular pressure in swimmers and cyclists (110), and increased mechanical loading and hepcidin release in response to subclinical exercise-related inflammation (97,105). Other factors affecting iron status biomarkers in athletes include regular nonsteroidal anti-inflammatory drug (NSAID) use, blood donation, and chronic alcohol consumption (12). Athletes with compromised iron status may experience decreases in performance because of the inability to optimally metabolize substrates into energy (51). Iron deficiencies also prevent adaptations to endurance and altitude training (11,60). Also, iron deficiency with anemia may have a role in the greater prevalence of upper respiratory tract infections in marathon runners (88). Given the physiological role of iron and its association with aerobic performance, health, and adaptation, athletes and coaches should consider tracking iron, iron binding capacity, transferrin saturation, and ferritin levels during training. Approaches to timing and frequency of iron status testing for individual athletes can be customized to address issues with when cardiovascular endurance performance may be affected by changes in training programs/cycles or general health (e.g., during infection or personal stress experienced during training). Iron status assessments acutely before competition will also be contextually useful. Practical considerations of cost of biomarker assessments may define frequency of testing.
The compliment of widely used biomarkers includes iron, total iron binding capacity (TIBC), transferrin saturation, and ferritin, with more recent biomarkers such as soluble transferrin receptor and hepcidin peptide assay possibly improving diagnosis. Iron status markers should be interpreted in the context of recent events (e.g., competition season, recent training intensity, frequency, and duration, inflammation state, and diet changes). Changes in iron status markers indicate a number of well-studied, potential effects on performance (Table 3).
Iron concentration reflects total iron content with a reference ranges within 50–175 μg·dl−1 (9). Between and within-day variation of iron concentration is high (10–26%) and as a consequence iron concentration must be interpreted cautiously and cannot be rendered a useful measure of iron status alone (15). Serum ferritin can be falsely elevated in an inflammatory state (e.g., postexercise, infection) but inflammatory markers such as C-reactive protein (CRP) or alpha-1-acid glycoprotein can aid in the interpretation of ferritin in the assessment of iron status (9). A more stable indicator of iron status is TIBC (reference range: 250–425 μg·dl−1), which reflects the total number of binding sites on the blood iron transporting peptide transferrin. Daily variation of TIBC is relatively low (8–12%) and does not change before iron stores are depleted (9), thus reducing the likelihood of falsely detecting iron depleted states. Total iron binding capacity would rise in iron deficiency as more free transferrin binding sites are available. In addition, transferrin is not an acute phase reactant or affected by other diseases and therefore is a valuable biomarker panel addition for determining iron status (152). Transferrin is an iron-carrying monomeric glycoprotein within blood that transports iron to tissues. Transferrin saturation (reference range: 15–50%) is the percentage of iron to TIBC, with values under 15% consistent with iron deficiency. Because TIBC is quite stable, alterations in iron concentration will also affect transferrin saturation (9). Soluble transferrin receptor reflects iron deficiency at the tissue level and is believed to be a more sensitive measure of functional iron deficiency assessed by ferritin (152). In 2 iron supplementation studies examining aerobic training adaptation in females, improvements were only noted when soluble transferrin receptor was elevated before training (>8 mg·L−1) compared with those with adequate iron status (<8 mg·L−1) (18,19). This biomarker seems not to be affected by inflammation and has low within-subject variability in athletes undergoing training. The combination of at least transferrin and transferrin saturation, TIBC, serum ferritin, and hemoglobin is required for accurate determination of the presence and severity of iron deficiency. Including additional clinical parameters such as soluble transferrin receptor, among others, may increase the confidence in iron status diagnosis.
Endurance performance suffers when iron levels are insufficient (serum ferritin <12 μg·L−1) for hemoglobin (Hb) to efficiently transport oxygen to exercising muscle tissue (Hb, females, <12 g·d−1; males, <13 g·dL−1). Yet, serum ferritin stores can be depleted before hemoglobin has declined to levels required for diagnosis of anemia (32). Functional iron deficiency has been defined as ferritin <35 μg·L−1, Hb <11.5 g·dl−1, and transferrin (iron transport molecule) saturation <16% (96); others have used more precise serum ferritin ranges of 12–20 μg·L−1. Iron deficiency without anemia is more common than iron deficiency with anemia in endurance athletes, but it is critical to consider multiple aspects of iron metabolism that may affect an athlete.
Supplementation with iron is known to correct low levels of ferritin, transferrin, and hemoglobin, but in some cases may not affect endurance performance (96). However, a vast amount of research supports that tracking these variables and introducing supplementation regimens is effective in improving endurance performance in athletes with low ferritin, both anemic and nonanemic (33,34,58,73,82,106,109,151). A recent review determined that in 73% of studies, implementing low-moderate doses of iron supplementation resulted in improvements in aerobic/endurance performance in female athletes (32).
Although biomarkers have been studied in human performance, there has been limited use of biomarkers to determine injury states (both risk for injury, severity of injury, and recovery from injury). No previous work, to our knowledge, has examined the use of biomarkers for injury prevention or for recovery after injury. Concussions are a major concern in sports. One of the major concerns in concussion is understanding when injured athletes have recovered. Previous work has examined biomarkers of concussion recovery with the goal of detecting and monitoring changes in the central nervous system to provide objective measures of when athletes are ready to return to athletic pursuits safely (111). Previous work in this area has focused on the examination of biomarkers in the cerebrospinal fluid, with specific emphasis on markers of axonal damage (total tau, neurofilament light), which have been shown to be elevated in boxers after repeated punches to the head even without a knockout (92,149). However, because of the invasiveness, difficulty, and expense of completing a lumbar puncture, researchers began to explore the possibility of assessing blood-based biomarkers of brain injury. Two blood-based biomarkers of interest have been neuron-specific enolase and the glial cell biomarker S-100 calcium binding protein B (S-100B), with most studies focusing on changes in S-100B levels (36,90,95,119–122). Serum levels of both markers have been reported to be increased after boxing matches in which the athlete sustained direct or repetitive blows to the head (50,150). By contrast, when examining these same markers in concussed hockey players, only S-100B was found to be increased in the serum (111). Based on this work and the 2015 review article by Papa, it is clear that the study of biomarkers of concussion is beginning to identify potentially diagnostic as well as recovery markers (99). However, no biomarkers have yet been identified for clinical diagnosis or tracking of concussions in athletic populations. This remains an active area for examination.
Another area of musculoskeletal health that has received substantial attention is stress fractures, specifically female stress fractures. Women had a 10-fold higher risk of sustaining a stress fracture when compared with men in a study of military recruits, and the risk has been reported to be as much as 50% higher in female athletes (10,41). Stress fractures are known to result in significant medical costs, lost duty time in the military, and lost game time for athletes. The female athlete triad is a medical condition that affects physically active females and is characterized by 3 components: (a) low-energy availability with or without disordered eating, (b) amenorrhea or menstrual dysfunction, and (c) low bone mineral density (BMD) (91). This condition has been associated with osteoporosis and low BMD, which have been proposed as risk factors for stress fracture development (41,102). Although specific biomarkers have not been associated with the female athlete triad, some biomarkers of bone breakdown have been associated with poor bone quality or bone density. Insulin-like growth factor (IGF-I), one biomarker associated with bone quality, has been reported to be significantly lower in osteoporotic women with poor bone quality and to be positively associated with BMD (87,116). In addition, reduced concentrations of IGF-I have been associated with fracture risk in women (64,125). Only a few studies have examined the use of biomarkers to assess stress fracture risk, none of which have identified a single set of bone turnover biomarkers that could be used for stress fracture prediction (124,147). However, Strohbach et al. (124) did report that serum IGF-I was decreased in subjects who sustained a stress fracture when compared with their noninjured control subject. The results of these few studies as well as an improved understanding of the female athlete triad will allow for the continued exploration of biomarkers that could potential identify individuals at risk of stress fracture development.
Anterior cruciate ligament (ACL) injuries have been reported to result in the development of osteoarthritis (OA) in up to 50% of patients (77). The development of OA in ACL patients has been reported to occur within 10–15 years of the primary injury (77,78,141). While the examination and exploration of both inflammatory biomarkers as well as markers of cartilage breakdown have been extensive in the study of OA, very few studies have explored these markers in ACL patients after injury and surgery; no studies, to our knowledge, have determined biomarkers that can be used to predict ACL injuries. The biomarkers of greatest interest in the early postoperative recovery period after ACL reconstruction have been serum concentrations of collagen type I and type II cleavage products as well as inflammatory responses in both human and animal models (55,127,132). Immediately after ACL injury, the serum concentration of these biomarkers indicates an imbalance between cartilage breakdown and synthesis that could be indicative of posttraumatic changes in cartilage metabolism and signal the onset of posttraumatic OA (127,132). Haslauer et al. examined changes in the IL-6, IL-8, markers of tissue damage (CRP), as well as vascular endothelial growth factor (VEGF), and transforming growth factor β (TGFβ) in Yucatan minipigs to examine the immediate response after ACL transection (55). The results of this study indicate that in the early postinjury period, there is an increase in IL-6 and IL-8 in the synovium as well as an increase in CRP in the ligament, whereas there was no change in TGFβ or VEGF. Similar to human studies, the CRP returned to normal levels by 15 days after injury or after surgery, wheras IL-6 and IL-8 returned to normal levels by approximately 5 days after injury or after surgery (21,55). In a study of ACL reconstruction patients, similar results were found regarding CRP, but this study reported an increase in TGFβ and myostatin in the early postoperative period and then returned to normal by approximately 12 weeks after surgery (84). Although these studies have identified biomarkers that change with injury and after surgical intervention, no studies to date have examined the potential for using biomarkers to identify individuals at increased risk. Thus, further research is required before these biomarkers should be assayed as a standard, clinical approach for injury assessment; it is important to note, that contextualized with results from other biomarkers, of muscle status for example, potential markers of injury like certain cytokines or CRP may be indicative of simply, exercise-induced muscle damage, or more seriously, overtraining. The overlap of biomarkers in many areas of diagnosis is one of the reasons that we suggest panels that will help define the true reason for changes in intersecting biomarkers.
Muscle damage is an expected part of exercise training, as are the physiological and immune responses that occur during and after muscle tissue damage. Athletes monitoring their performance during training may track inflammation indirectly through key components of the inflammation process that can enter systemic blood circulation. Chronic inflammation that persists after damage results from positive feedback of multiple signals indicating injury or stress from overtraining, or results from infection/illness can also be tracked in specimens by assessing proteins and other molecules that control inflammation (Figure 3). Chronic inflammation can also result from infection, autoimmune disease, cardiovascular disease, or other major health concerns. In both instances, chronic inflammation is a positive feedback phenomenon that can impact health and performance of an individual. Creatine kinase, for example, is released in response to skeletal muscle damage or cardiac muscle damage during myocardial infarction. Creatine kinase levels have remained a valuable biomarker for muscle damage despite several limitations, including individual variability in CK response to damaging exercise (140), the need for information on CK isoforms to determine whether elevated CK is due to cardiac or skeletal muscle damage (30), and other complicating factors. In addition to CK, myoglobin released is a more of a short-term marker of damage measurable in blood (117). More specific markers including skeletal muscle troponin I, skeletal muscle specific enzymes, and markers indicating an oxidative stress-antioxidant response during muscle damage have also been extensively reviewed and used to track muscle damage during exercise (17). Concurrently measuring muscle damage markers when assessing biomarkers of inflammation in an athlete is critical to contextualizing the potential source of inflammation and define the subsequent action required for athlete health and optimal performance.
As markers of muscle damage are released into circulation, at the tissue level resident or locally surveying naive immune cells migrate to the site of tissue injury and differentiate into mature proinflammatory macrophages that function to phagocytose and clear debris and degenerate damaged tissue. Mature activated macrophages also release a number of growth factors, cytokines, and other signaling molecules to promote the inflammatory process by recruiting other cells required for skeletal muscle regeneration to differentiate and function in repair. As inflammation progresses, macrophages convert to anti-inflammatory profiles and release different growth factors, cytokines, and have distinct effects to encourage the progression of repair stages. Shifts in circulating immune cells as cell populations move in and out of tissue vs. systemic circulation can be measured through a complete blood count with differential (CBC/diff). Although the CBC/diff assay cannot be used alone to assess an athlete's level of inflammation, it is another assay that provides valuable information about shifts in immune cell populations that may occur during muscle damage-induced inflammation. Another benefit of assessing CBC/diff profiles in athletes is that CBC/diff can be used to diagnose potential infection or disease that might also cause inflammation and increases in biomarkers that are common with muscle damage-induced inflammatory biomarkers. Additional recruitment of monocytes or other immune cells during inflammation can be tracked using blood measures of chemicals that attract immune cells to an area (e.g., monocyte chemoattractant protein-1 or soluble intracellular adhesion molecule-1) while activation of other immune cell types can be measured through cellular components like CD40 ligand (CD40L, CD154) that are only expressed or released as soluble factors by activated immune cells.
The blood biomarkers that indicate proinflammatory macrophages activity include growth factors and cytokines released by macrophages. The most standard of these are generalized signaling molecules termed “cytokines.” Cytokines are numerous and diverse in function, making it difficult to use the presence of these alone as a direct measure of inflammation in an athlete. However, we can assess inflammation through increases from an individual's normal baselines in cytokines classically considered proinflammatory such as IL-1β, TNF-α, IL-6, IL-10, IL-8, and IL-12p40. There is no recommendation for a threshold above which increases in inflammatory markers are universally interpretable as “elevated.” The recommendation is to use repeat testing at rested, healthy baseline states to establish individual reference ranges for normal values, and also test at key changing points in training, health status, performance status during competition, and heavy training periods to determine what are normal fluctuations in inflammatory markers, and which are fluctuations and values associated with physical concerns. This dynamic approach to biomarker testing begs coaches and athletes to use biomarker testing to observe normal changes in biomarkers during healthy states and document dramatic changes in biomarkers that are associated with performance effects. This may require a period of adjustment during which biomarker testing is essentially calibrated to each individual, but this approach will provide the greatest accuracy and precision independent of the biological diversity that we know occurs among all individuals.
Hallmarks of prolonged, severe inflammations include markers of tissue damage associated with chronic inflammation. One aspect of prolonged or severe inflammation involves hepatic signaling by circulating cytokines. During inflammation, liver tissue may be stimulated to produce an acute phase response. The acute phase response and acute phase reactant proteins produced by the liver trigger a systemic inflammation response that recruits vascular tissue activation, systemic immune response, endocrine function, and other multiorgan involvement in positive feedback of inflammation. Classic acute phase reactant proteins that are measured include CRP, serum amyloid A, E-selectin, von Willebrand factor (endothelial dysfunction), plasminogen activator inhibitor-1, fibrinogen, P-selectin, and inflammatory cytokines.
Because muscle damage, inflammation, and acute phase response may normally occur during exercise training designed to optimize performance, it is critical to contextualize assessment of inflammation biomarkers with other assays concurrently. For example, the assessment of CBC/diff could indicate the presence of an infection that is temporary and requires no long-term change in an exercise training program. Chronic or prolonged inflammation should be evaluated with such markers that might indicate chronic disease states that will direct long-term and dramatic changes in training. Additional markers that overlap with other aspects of an athlete's health will also provide valuable information about action from insight. An athlete that consistently and chronically exhibits high levels of inflammatory markers should also, for example, be evaluated for chronic stress, which can be tested for by physical assessment of fatigue or performance decrements, subjective perceptual scales, or assays measuring levels of stress hormones such as cortisol (48,72,134). We reiterate the recommendation that repeat testing during rested, healthy states will provide average values for each individual, as markers of inflammation may be highly varied person to person, and establishing per-individual reference ranges will be most practical and useful.
To better understand the dynamic and integrative aspects of how diet, hydration, training, and competition affect athletes, assessment of biomarkers should include select, diverse, and well-validated markers of performance (muscle status and oxygen transport), health (nutritional and hydration status, allergies), and recovery (inflammation, injury risk, muscle damage) (Figure 1). Because many validated biomarker reference ranges are appropriate for generalized populations rather than for athletes, repeat measurements will allow each clinician/coach to establish personalized reference ranges; from these individualized “normal” values that may fluctuate day-to-day or week-to-week, an athlete or sports professional can track chronic changes in directions that are associated with risk of injury, overtraining, or decreased performance. We have provided examples of useful biomarkers. It is important that the coach and athlete determine priorities for tracking training and competition and adapt their biomarker panels accordingly. As new biomarkers are being tested and validated, researchers will identify more universal, consistent biomarkers of multiple aspects of athlete health and performance.
E. C. Lee, S. A. Kavouras, R. M. Queen, J. L. Pryor, and D. J. Casa are members of the Quest Diagnostics' Sports Science and Human Performance Medical and Scientific Advisory Board. M. S. Fragala is an employee of Quest Diagnostics. No grant support contributed to the development of the manuscript. The content of the manuscript does not constitute endorsement of a product by the authors or the NSCA.
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