Are Acute Post–Resistance Exercise Increases in Testosterone, Growth Hormone, and IGF-1 Necessary to Stimulate Skeletal Muscle Anabolism and Hypertrophy?

PREVAILING PERSPECTIVE Acute post–resistance exercise (RE) increases in anabolic hormones may not be “necessary” to stimulate skeletal muscle anabolism and hypertrophy; however, as we will support in the following discussion, post-RE increases in these hormones are “optimal” for maximizing skeletal muscle anabolism and hypertrophy. For purposes of this presentation, increases in testosterone (T) and growth hormone (GH) will also imply increases in insulinlike growth factor 1 (IGF-1) (22,24). Furthermore, we will limit the discussion of these adaptations to men, while recognizing that training variables such as training history, mode, intensity, volume, and rest interval (RI) length in between sets will have compelling influence on the hormonal responses to RE. DEFINING THE SCOPE Studies examining the influence of acute RE-induced T and GH responses on skeletal muscle anabolism have included both trained and untrained young (18–30 yr) and older (60–80 yr) men. Regardless of trained state or age, substantial evidence indicates RE protocols and short-term resistance training (RT) using two to four sets, 8–15 repetition maximum (RM), ≤2-min RI, and RE that activates large muscle masses (i.e., multijoint movements) elicit the greatest acute elevations in T and GH (1,2,6,14,21,23,24,26,27,33,35,42). Further, recent evidence suggests strength RE protocols and short-term RT prescribed using 1) two to eight sets, 3–6 RM, ≤90-s RI, with multijoint movements (42); or 2) five sets, 3–5 RM, 3-min RI, followed by an additional set of a 25–35 RM, after a 30-s RI (13,14) elicit significant elevations in T and GH. Therefore, there is strong evidence that RE can result in substantial postexercise elevations in anabolic hormones. So the question posed is, “Do these acute RE-induced elevations in T and GH translate into skeletal muscle anabolism and hypertrophy?” SUPPORTING STUDIES The following investigations incorporated dissimilar methodologies but provide strong evidence in support of the prevailing perspective. Three studies were selected that used short-term RT interventions and examined the influence of physiologically elevated acute hormonal responses on human skeletal muscle (13,26). Two studies were selected examining the effects of physiologically elevated acute T on molecular mechanisms initiating skeletal muscle anabolism (35,49). Kvorning et al. (26) investigated 22 recreationally active, untrained men, 20–30 yr. The endogenous production of T was suppressed by the use of a GnRH agonist (goserelin) compared with a placebo group (unaltered endogenous T levels). Both groups performed identical 8 wk of total body RT programs: 3 d·wk−1 training frequency, sessions 1–8 (3–4 × 10 RM, 2-min RI), sessions 9–16 (3–4 × 6 RM, 3-min RI), and sessions 17–24 (3–4 × 10 RM, 2-min RI). Two-thirds of the program was hypertrophy training, designed to elicit acute elevations in T and GH (24,27,42). Study participants in the placebo group experienced significant acute elevations in T and GH in response to at least 16 of the 24 total training sessions, whereas those in the goserelin group did not experience acute elevations of T in response to any of the training sessions. The lean mass increases in the legs were greater in the placebo group compared with the goserelin group (P < 0.05). Furthermore, the clinically important increases in total body lean mass revealed a strong trend (P = 0.07) toward statistically significant differences between the two groups. These findings demonstrate an implicit link between endogenous T, both resting levels and the magnitude of acute responses to RE, and the hypertrophic adaptation to short-term RT. Goto et al. (13) evaluated 17 untrained men, 19–22 yr, performing leg press and leg extension exercises 2 d·wk−1 and compared the effects of a 4-wk periodized combination-type RT program (5 × 3–5 RM; 3-min RI; sixth set, 25–35 RM, after a 30-s RI after the fifth working set) to a 4-wk periodized strength RT program (5 × 3–5 RM; 3-min RI), after a 6-wk periodized hypertrophic RT program performed by all study participants (two rounds of 3 × 10–15 RM, 30-s RI, 3-min rest in between rounds, and 3- to 5-min rest in between exercises). Combination-type RE induced significantly greater acute increases in GH compared with strength RE (14). During the final 4-wk phase of training, CSA increased in response to combination-type RT and decreased in response to strength RT (P = 0.08 between groups). This evidence suggests that muscle CSA may be augmented by enhancing the acute GH response through performance of a single set of low-intensity, high-repetition exercise, immediately after repeated sets of high-intensity, low-repetition exercise, during short-term RT. In the third study, our laboratory recently completed an investigation of 22 recreationally active men, 64–72 yr (unpublished results). Participants performed free weight– or machine-based total body RE protocols, with a 3 d·wk−1 training frequency. We compared the effects of an 8-wk periodized strength RT program using short RI (SS) (2–3 × 4–6 RM; 60-s RI) to the same 8-wk periodized strength RT program using extended RI (SL) (2–3 × 4–6 RM; 4-min RI), after a 4-wk periodized hypertrophic RT program performed by all study participants (2–4 × 8–15 RM; 60-s RI). Strength RE protocols with short RI induced significantly greater acute increases in T and GH compared with strength RE protocols with extended RI. Across the final 8-wk RT phase, total body lean mass increases were greater in response to SS compared with SL (P < 0.05). This finding suggests that lean mass gains are enhanced by acute elevations in T and GH through the use of short RI within short-term strength RT. Willoughby and Taylor (49) examined the effects of acute increases in T across three sequential hypertrophic RE bouts, separated by 48 h, on skeletal muscle androgen receptor (AR) mRNA and protein expression as well as myofibrillar protein content in nine young men (17–21 yr). T was elevated after all three RE bouts (P < 0.05). AR mRNA and protein were elevated 48 h after bouts 2 and 3 (P < 0.05) and correlated with acute RE-induced increases in T immediately post-RE (P < 0.05). Lastly, myofibrillar protein content was elevated 48 h after bout 3 (P < 0.05). These findings suggest that repeated exposure to RE-induced increases in T mediates upregulation in acute AR expression and subsequent increases in myofibrillar protein, possibly because of enhanced ligand-binding capacity and via the T-AR signaling pathway. Spiering et al. (35) investigated six men, 22–30 yr. All study participants performed a control RE protocol (bilateral knee extensions, 5 × 5 RM, 90–95% 1RM, 3-min RI) and a high-T RE protocol (upper body protocol [4 × 10 RM, 80% 1RM, 2-min RI], immediately preceding the same control RE protocol). Acute T responses were significantly greater with the high-T RE protocol compared with the control RE protocol. Muscle tissue analysis revealed only the high-T RE protocol potentiates AR responses to acute RE. RE-induced acute elevations in T prevented catabolism of muscle AR content post-RE, via enhanced AR mRNA translation and increased AR half-life. This evidence suggests RE prescription that maximally elevates T will likely optimize hypertrophic adaptations to RT via enhanced T–AR interactions. STUDIES WITH OPPOSING PERSPECTIVE Investigations in men with prostate cancer receiving androgen deprivation therapy (castrate T levels) and participating in RT programs have demonstrated significant improvements in muscle mass and strength; however, these gains are modest at best (10). Wilkinson et al. (48) evaluated 10 men, 21–22 yr, performing an 8-wk RT program, 3 d·wk−1 training frequency, with unilateral leg press and knee extension (three sets, 6–10 RM, 80–90% 1RM, 3-min RI). The 8-wk RT program did not elicit significant acute changes in T, GH, or IGF-1. CT scans revealed significant increases in muscle CSA. These findings suggest unilateral RE that does not induce significant acute elevations in T, GH, or IGF-I may still stimulate muscle hypertrophy. However, it is difficult to determine whether this anabolic response is “optimal” because we know that both RE and T supplementation independently stimulate skeletal muscle hypertrophy and that the combination of RE and T supplementation results in an even greater anabolic response (3,26). SUMMARY Dismissal of the role of RE-induced elevations in anabolic hormones to maximally stimulate skeletal muscle anabolism and hypertrophy appreciably understates the importance of these hormones to the physiological mechanisms responsible for hypertrophic adaptations to RT. The aforementioned studies supporting the prevailing perspective demonstrate that acute endogenous increases in anabolic hormones, as well as their influence on skeletal muscle receptors and resulting hypertrophic response, are critical to optimizing RE-induced adaptations and, thus, health and performance across the lifespan. REPLY TO CHALLENGING VIEW Post-RE elevations in anabolic hormones may not be “necessary” to promote some degree of skeletal muscle anabolism after an RT program, and a review of recent literature suggests that the research is inconclusive as to whether or not the post-RE anabolic hormonal response plays a significant role in skeletal muscle hypertrophy (32). We maintain that these elevations are critical to optimizing hypertrophic and strength gains as part of an integrative response to well-designed and applicable RE stimuli, leading to chronic functional improvements in skeletal muscle mass and force production. Phillips et al. have proposed a unique “low and high” hormone exposure model to study the influence of acute changes in T, GH, and IGF-1 after RE and chronically with RT (43,44); however, their model includes supplementation with whey protein before and/or after RE albeit in both the low and high hormone groups. We contend that the inclusion of a protein supplement in this study design is a major confounding factor because it is well known that amino acids are potent hormone secretagogues that inhibit muscle protein breakdown and stimulate muscle protein synthesis, modulating skeletal muscle hypertrophy (20,28,41). The anabolic implications of protein supplementation are well documented (7,50). Dillion et al. (7) demonstrated that older women who have negligible circulating T and were not exposed to RE received amino acid supplementation for 3 months and had significant increases in basal muscle protein synthesis and increases in lean body mass, demonstrating the potent influence of amino acid supplementation on skeletal muscle anabolism, even in the absence of RE. In fact, Phillips et al. reported similar findings in young women with greater gains in muscle mass and strength when consuming fat-free milk post-RE compared with carbohydrates (19). Furthermore, the ingestion of casein and whey proteins 1 h after an RE bout results in greater muscle anabolism compared with the ingestion of a placebo after RE (40). Therefore, it could be argued that supplementation with protein in combination with an RE model may mask potential enhanced effects mediated by acute increases in anabolic hormones because of the powerful influence of amino acids on molecular transcription and translation processes involved in skeletal muscle protein synthesis. Sex-based comparisons of myofibrillar protein synthesis after RE, with or without post-RE nutrient ingestion, emphasize two major concerns: 1) protein synthesis measured after an acute bout of RE (46) does not always occur in parallel with chronic upregulation of causative myogenic signals (5) and 2) it is not necessarily predictive of long-term hypertrophic responses to RT programs (39). In addition, circulating T levels are approximately 10-fold higher in men compared with women, and this is believed to be the primary rationale why men display substantially greater postpubescent muscle mass (18). Lastly, older women with low basal T levels display blunted increases in maximal strength and hypertrophy compared with those with higher T concentrations (15,16). Phillips et al. previously reported that RE shortens the duration (<28 h), for which muscle protein synthesis is elevated after exercise (38). Yet they have designed an RT program (44) where participants trained once every 72 h for weeks 1–6 and once every 48 h for weeks 7–15, resulting in an average of less than two (1.87) RE sessions per week. From an applied perspective, this frequency of training stimuli is inadequate and likely related to the minimal growth experienced by both training groups. If the acute training stimulus for a hypertrophic adaptation is lacking because of an inadequate RE scheme design, it becomes difficult to justify the lack of RE-induced hypertrophy, let alone identify mechanisms contributing or not contributing to the chronic adaptive response. Lastly, the selection of elbow flexor musculature should be challenged (44,46). How relevant is elbow flexor hypertrophy? How much additional growth can be experienced by such a small muscle mass in response to RT? We contend that the majority of RE protocols relevant to applied professions inevitably induce transient elevations in anabolic hormones, specifically training multiple compound movements before isolation movements within a single RE bout (at least 4–6 movements total), using moderate to high volumes, moderate to high training loads, and short rest interval lengths in between sets. We believe that investigations of adaptations elicited by RE protocols that are not of value to clinicians or strength and conditioning professionals considerably limits the meaningfulness, applicability, and clinical relevance of the findings. CONCLUDING STATEMENT The anabolic hormonal milieu is necessary to maximize functional adaptations to RT. Although post-RE elevations in anabolic hormones may not be necessary to acutely stimulate muscle protein synthesis or promote hypertrophy of small muscle masses, these elevations in anabolic hormones are ideal to optimize functional performance gains in whole body skeletal muscle mass and strength in men and women across the lifespan. CHALLENGING PERSPECTIVE A pervasive view in the area of endocrine responses to resistance exercise is that acute postexercise hormonal responses of testosterone, growth hormone (GH), and insulinlike growth factor 1 (IGF-1) are critical for subsequent skeletal muscle anabolism. If this is the case, then exercise regimes can be manipulated to enhance hormonal responses and thus enhance skeletal muscle adaptations such as strength and muscle mass gain. Despite this alluring prospect, we contend that postexercise increases in testosterone, GH, and IGF-1 are not necessary to stimulate skeletal muscle anabolism and hypertrophy and that measurement of the responses of these hormones yields little in the way of insight into longer-term resistance training-related adaptation. Despite the prevalent view (25) that hormones hypertrophy, there is a lack of supporting evidence for this In fact, Wilkinson et al. (48) significant gains in strength and hypertrophy in the absence of any changes in free testosterone and IGF-1. we two studies to whether elevations in testosterone, GH, and IGF-1 were necessary for or could enhance muscle anabolism. We used a study design in which the elbow were to hormone concentrations or high hormone concentrations that were the result of an body exercise We used this “low and high” hormone exposure model to the effects of postexercise hormone concentrations on muscle anabolism acutely (46) and chronically with resistance training In both whey protein was postexercise to provide for any potential anabolic responses by the low and high hormone that in the absence of postexercise protein does not In the low hormone myofibrillar protein synthesis was elevated and gains in strength and hypertrophy after training, testosterone, GH, and IGF-1 concentrations that were similar to basal is, postexercise increases in testosterone, GH, and IGF-1 were not necessary to stimulate anabolic processes as we had reported previously Furthermore, when testosterone, GH, and IGF-1 were elevated there was of myofibrillar protein synthesis acutely or gains in strength and hypertrophy with our acute findings (46) we in a chronic training study can be that muscle protein synthesis is measured acutely because it is the primary of enhanced muscle protein anabolism that after resistance exercise and to the proposed and of protein the of repeated of enhanced protein after exercise and amino acid result in hypertrophy. A study that was similar in design to our (44) reported findings that that elevations in endogenous hormones adaptations in strength and some of hypertrophy. a proposed for the findings between studies was that the exercise in our study may have a because our participants trained their before their it was that the body may have the and adaptation Therefore, we recently measured and testosterone, GH, and IGF-1 concentrations to hormone to the elbow when they were trained before or after leg exercise We differences in the hormone and thus evidence that the anabolic were because of the lack of hormone to exercise of evidence to support the that testosterone, GH, and IGF-1 are important of muscle anabolism. of of hormones and gains in strength and hypertrophy in a large that hormone responses did not for in training adaptations in strength or hypertrophy Furthermore, gains in strength and hypertrophy by high and low were not by their hormone response. In a study we demonstrated that women, who a postexercise testosterone response for elevated myofibrillar protein synthesis to a similar as men. is, not the of postexercise testosterone, women were to a in of myofibrillar protein synthesis, which should have testosterone was necessary to the postexercise anabolic response. We view these as support of a in which mechanisms that are to the muscle and not on hormonal are responsible for hypertrophy. et al. demonstrated that GH which GH and IGF-1 does not stimulate myofibrillar protein synthesis but synthesis of is whether could also be synthesis and thus which be in supporting a muscle as the result of resistance From a in our studies of elbow flexor hypertrophy, the high did not result in any in or muscle or functional or 10 or that we measured a low Therefore, there was some in the of the tissue between it had to strength or hypertrophy. We know that GH does not the For GH and area the are greater after at than after resistance exercise the of these and studies by et al. it is difficult to a by which transient in GH or IGF-1 hypertrophy. In to GH, testosterone is in to stimulate hypertrophy; however, in an is the anabolic of The anabolic of testosterone are and as a rationale for the measurement of postexercise hormonal which are as a for the anabolic potential of skeletal However, a is that muscle mass during testosterone is related to androgen which is the of both and duration 1 this and why the to endogenous testosterone is a the transient of testosterone is compared with the increases in testosterone with which a higher androgen and that results in muscle hypertrophy A of the of testosterone testosterone a of the of testosterone a and the of a after a on to testosterone testosterone area the on in not to have all the of the endocrine response to resistance For the of GH (25) alone may always they are but this is a skeletal muscle receptors for all these not also there are of resistance exercise program all of which could hormonal we that the hormone that we used for the mediated responses to be in then are the implications of a that is not by From an applied it that exercise programs not to be designed on hormonal that large muscle group exercises not to be with small exercises for the of the hormonal response. From a hypertrophy that with resistance training is mediated by processes as to hormonal responses as causative or in hypertrophy, are an area that we view as REPLY TO PREVAILING PERSPECTIVE We with and of evidence that greater hormonal responses provide an “optimal” anabolic of we not with their that acute exercise increases in anabolic hormones may not be necessary to stimulate hypertrophy. This that mechanisms can the hypertrophic response. and by that purposes of this presentation, increases in testosterone (T) and growth hormone (GH) will also imply increases in This is because GH responses are and related to large muscle masses whereas IGF-1 responses are This is by examining the two studies that the as for the IGF-1 demonstrated significant increases rest in both and in response to both The a and of of did not changes Furthermore, whereas an exercise protocol of 10 and 1 rest a greater GH than protocols, IGF-1 was Therefore, changes in postexercise IGF-1 be by changes in postexercise GH. to the there is little evidence that GH mediates gains in strength and hypertrophy at through IGF-1 or as by studies that are not to however, GH does not enhance myofibrillar protein synthesis or hypertrophy The we will limit the discussion of these adaptations to This is but we that the that women are is that they not the For a testosterone response than men women similar and hypertrophy responses compared with men. and studies were selected that short-term RT interventions and examined the influence of physiologically elevated acute hormonal responses on human skeletal (13,26). and the of Goto et al. (13) who were in this a role in of the circulating of GH much a study in which testosterone was to concentrations that were chronically We with the that this is an that is of the of physiological acute hormone responses on hypertrophy in the following the third study is an study by and laboratory and thus be and on research of relevance to the a resistance training study in cancer this testosterone to levels 24 h a it is for those that gains in strength and hypertrophy, that are similar to gains in can still be by using high resistance exercise protocols even by and to have as to the insight they For Willoughby and Taylor (49) compared resistance exercise to a Spiering et al. (35) in androgen receptor content at of two postexercise but because androgen receptor content was the in that study, it is to determine whether these findings have implications for hypertrophy. we view and of the studies to be lacking in support for the question posed in some and as in and their perspective to a by two studies Although in our these studies have little to with whether or not physiological postexercise mediates hypertrophy with resistance is, testosterone to levels (26) or testosterone to are not that to androgen are why elevations or of testosterone be used to relevance to transient postexercise elevations in postexercise hormonal concentrations are compared with the or in interventions hormone concentrations are greater than those that occur in and is by testosterone that have and and receptor endogenous and not transient hormonal changes We using to changes in androgen exposure hypertrophy. to during but resistance training can (26) or hypertrophy elevations in testosterone postexercise have a negligible on androgen exposure 6 and are and hypertrophy. induced muscle resistance training the in muscle In or little to hormonal we to the relevance of that these as of the question that was a that is on androgen exposure why transient elevations in testosterone not have a significant on changes in testosterone basal hypertrophy 6 and postexercise testosterone high within a physiological a negligible on androgen exposure and hypertrophy. resistance androgen deprivation testosterone with et al. at young men resistance exercise et al. with Kvorning et al. et al. average of low hormone et al. (44) and average of high hormone et al. and et al. research is to determine the of the between STATEMENT is to the for studies that only postexercise hormonal responses and a potential on hypertrophy. We that the evidence for such an lacking and the lack of evidence that hormones are important in hypertrophy after resistance and androgen are not which to the of changes in hormonal concentrations on hypertrophy. of of Phillips of

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