The adrenergic response is related to the sympathetic nervous system (SNS) and the associated neural stimulation of the adrenal medulla in response to stress, including resistance exercise. High-intensity and/or high metabolic stress caused by a resistance training workout can dramatically increase the sympatho-adrenal responses with high elevations in the concentrations of catecholamines (i.e., epinephrine, norepinephrine, and dopamine) and sympathetic stimulation (norepinephrine). The adrenal medulla releases predominately epinephrine and its response can be related to the demands of resistance exercise as to its volume and intensity of the workout protocol or the metabolic demands as represented by the changes in blood lactate. High levels of adrenergic stress as seen in extremely short rest period (1 min or less between sets and exercises) workouts using light-to-moderate resistances or higher volume and high-intensity workouts also can result in increases in cortisol concentrations in the blood [15–17] due to the influence of epinephrine on the adrenal cortex via a portal circulation. Therefore, cortisol’s response may go into recovery but can be maintained for longer periods of time, thereby negatively influencing other cell and tissue recovery time courses if not mitigated to resting concentrations [13].

Muscle fibers that have not been recruited may also be susceptible to the effects of cortisol, which is released from the zona fasciculata of the adrenal cortex in response to exercise stress. Cortisol alters protein balance by inhibiting muscle protein synthesis and increasing muscle protein degradation, which has been attributed to activation of the ubiquitin pathway [18]. The impact of this glucocorticoid response is substantial as it leads to a decreased synthesis of actin and myosin heavy chains [19]. Furthermore, it is primarily type II muscle fibers that are degraded in response to increased concentrations of cortisol [20, 21], which coincidently are exactly those fibers that will not be recruited if the load lifted is not heavy enough. In addition, it can block downstream anabolic signaling of the Akt/mTOR system [22].

Resistance training programs that produce the highest blood lactate concentrations appear to produce the highest cortisol concentrations in both men and women [23–26]. As heavy resistance training that is capable of fully recruiting type II muscle fibers can significantly increase salivary cortisol concentrations over non-exercising controls, so too can resistance training programs that are not capable of full recruitment, such as 60 % 1 RM [27] and 80 % of 12 RM [28]. In such circumstances, where heavy resistance training is capable of inducing maximum recruitment of motor units, light resistance training will not only fail to recruit type II muscle fibers and prevent their adaptation, but again such fibers will also be exposed to the catabolic effects of cortisol that were previously discussed as part of the impairment related to prolonged chemical damage influences (e.g., free radicals and elevated cortisol).

Also, not only do heavier resistance training programs have the important benefit of inducing full activation, but a significant testosterone response has also been consistently observed in response to heavy resistance training [15, 23, 28, 29], which can mitigate the negative effects of elevations in circulating cortisol. Interestingly, although some studies have observed an elevation in cortisol in response to heavy resistance training [23], others have not [28]. As a result, at the very least, testosterone would be able to mediate the cortisol response, but may even stimulate anabolic processes with minimal opposition from catabolic processes. Interestingly, resistance-trained women (not taking oral contraceptives) showed an elevation of the glucocorticoid receptor content concentrations in the muscle after heavy squat exercise (6 sets of 10 RM with 2-min rest periods) followed by a decrease 70 min into recovery [30]. In contrast, resistance-trained men were unresponsive as to receptor content changes but exhibited significantly lower glucocorticoid receptor concentrations indicating a potential sex difference in managing increases in acute cortisol concentration signals [30].

The take-home message regarding activation is that heavy loads are required to fully recruit type II motor units. If the motor units are not recruited, they will not adapt as a primary target of resistance training and almost all changes in connective tissue are mediated via the muscle with further importance related to the exercise variables such as resistance used and metabolic stress. Furthermore, if a resistance training program is designed in such a way that light loads are lifted but rest periods are short and volume is high, a cortisol response could damage those type II motor units that were not recruited in the processes that results from exposure to reactive oxygen species. Chronic use of extreme type programs may also increase the inflammatory levels in the body along with chronically elevated cortisol if cybernetic recovery of the adrenal cortex is not allowed. Constructs of adrenal exhaustion also appear if programs are not periodized (i.e., program variation of stress) and adequate recovery days are not allowed [31].

Testosterone is a steroid hormone synthesized from cholesterol in the Leydig cells, which are found in the testes in men. Despite no presence of Leydig cells in women, testosterone can also be produced in the ovaries as well as the zona reticularis of the adrenal cortex, which explains the presence of testosterone in women, albeit at much lower concentrations. Despite some confusion due to the androgenic role played in male biology, androgens including testosterone play important roles in women’s anabolic signaling [32]. Although it is well known for its role in secondary male sex characteristics such as beard and body hair growth (also known as androgenic effects), in muscle it is a potent stimulus of muscle hypertrophy (anabolism). These effects are so strong that they have led to the production of drugs known as anabolic-androgenic steroids, which are synthetic derivatives of testosterone designed to reduce the androgenic effects of the hormone while continuing to promote the anabolic effects [33]. Such drugs, also known simply as steroids, have been outlawed by the World Anti-Doping Agency, but continue to be used recreationally and in competitive sports. This serves to highlight the powerful effects of testosterone and its derivatives on muscle anabolism.

Anabolism is promoted by testosterone by stimulating muscle protein synthesis [34] as well as reducing protein degradation [35]. The anabolic effects of testosterone are attributed to a translocation of the androgen receptor (AR) to the nucleus in response to testosterone binding, where the now-formed AR–testosterone complex increases gene transcription [36]. In terms of its anti-catabolic effects, testosterone appears to inhibit the glucocorticoid receptor [37], thus preventing processes such as the activation of the ubiquitin pathway as discussed earlier.

As mentioned, anabolic-androgenic steroids have been used to increase circulating testosterone concentrations. However, there is also a natural stimulus for testosterone release as a part of a resistance exercise stress signaling response in both men and women, albeit at 20–30-fold lower concentrations in women [26, 38]. While an increase in testosterone is not mandatory for many resistance training adaptations, it is part of a signaling process from the Hz depolarization of the motor units to AR cascade in muscle [30, 39]. Nevertheless, the amount of testosterone released in response to resistance training is governed by age and sex as well as the manipulation of what has been termed the acute program variables. These variables include intensity, number of sets, rest period, choice of exercise, and exercise order. A full review of the impact of these variables on testosterone is available in [40]. In brief, higher intensity (defined as a percentage of 1 RM) resistance exercise, providing an adequate number of sets are reached appears to significantly induce a testosterone response. Likewise, the use of high numbers of sets induces a testosterone response, but only when a threshold for intensity is met. Furthermore, resistance exercises that recruit more overall muscle mass (such as Olympic lifts) induce a testosterone response, whereas when small muscle groups are exercised, even if vigorously, a testosterone response is not seen. However, the homeostatic signal is dependent on the binding of the hormone with a receptor. With other stimuli in existence, changes can occur without increases in testosterone (e.g., increases in strength with heavy 2–3 RM squat training loads). However, such an exercise stimulus would also increase androgen binding with existing concentrations of testosterone in circulation.

The interpretation of circulating testosterone has been one of confusion and controversy as it is only part, albeit an important part, of a large array of signaling sets of pathways. An increase might well be only one factor in the upregulation of ARs. The voltage amplitude involved in depolarization of motor units (especially heavy resistances, e.g., 90 % and greater) may well be the other primary influence increasing anabolic signaling for the regulation of ARs despite no apparent elevation in the circulating concentrations of testosterone. Furthermore, nutritional intakes may be the final stimulator of ARs as protein/carbohydrate intakes result in higher upregulated AR content than fasted conditions [41]. The increase in AR content in the muscle was explained by the decrease in circulating testosterone (almost 50 % of the shared variance) demonstrating the impact of ARs to modulate concentrations of testosterone [41]. This shows the difficulty of interpretation without adequate context for the circulating values (e.g., nutritional intakes and timing). Thus, the theory of how testosterone influences muscle depends on a combination or potential integration of a number of factors from the resistance exercise stimulus to provide testosterone increases, to the level of the voltage that is involved in the depolarization of motor units (intensity to number) for sarcolemma membrane preparation (e.g., electrical gating mechanisms, protein pits activated, and beta 2 receptors activated by epinephrine), to the use of nutritional intakes (e.g., amino acid and glucose availability) around the workout resulting in a decrease in testosterone concentrations due to upregulated increased androgen content available for testosterone binding in muscle. Thus, several dimensions of this appear to be operational depending on the context of the scenario. From a sex-linked characteristic, in response to the same relative resistance exercise protocol (6 sets of 10 RM with 2-min rest periods), women with lower testosterone responses stabilize, downregulate, and then upregulate their ARs in muscle at a much more rapid rate (i.e., within an hour) compared to men who might take up to 2–6 h potentially due to processing higher concentrations of testosterone in the process.

When comparing an 8-week resistance training program among young men, Kvorning et al. [42] demonstrated that young men whose endogenous testosterone concentrations were blunted by a drug (i.e., given the drug, goserelin) failed to increase strength and lean mass in contrast to a placebo group (no pharmaceutical blocking of LH pulse). The experimental group also increased body fat percentage whereas the placebo group decreased. Thus, in young men, testosterone plays a paramount role beyond other signaling systems in its natural homeostatic concentrations and as a potent signal for anabolic functions [43]. Furthermore, if strength and lean mass gains were drastically affected, then other processes that have been highlighted here (growth hormone, GH, and insulin-like factor, IGF) while fully operational are not as dominant in young men as testosterone as a major signaling effect. In young women, testosterone has been associated with the regional fat distribution in the body due to its significant role in adipocyte alterations [38]. With older men, although testosterone is an important signaling hormone, other hormonal mechanisms (e.g., GHs and IGFs) as in women may start to play an endogenously greater role in adaptive mechanisms. Nevertheless, in larger population studies, free androgen index has been associated with muscle mass and strength in men and women over 50 years of age and dehydroepiandrosterone sulfate (DHEA-s) concentrations were related to muscle size, strength, and functional outcomes such as gait speed [44].

First, growth hormone (GH) is not just one single hormone, but actually a family of hormones with over 100 variants and aggregate combinations [45, 46]. In addition, the concentrations of 22 kD in blood is but a very small portion of the concentrations of the total aggregate concentrations (e.g., 4–30 ug/L for 22 kD under various conditions vs. 2000–15,000 ug/L of aggregate under various conditions) [46]. The specific role of each variant, isoform, or aggregate is yet to be determined, but resistance training has been shown to be a potent stimulant of many of these variants (e.g., aggregates of binding proteins and/or various combinations of aggregates of the 22-kD monomer as well as splice variants of the 22-kD monomer), with acute increases following single exercise bouts as well as chronic elevations from long-term resistance training programs [47] . Typically, women demonstrate higher GH concentrations than men in the limited data from the early follicular stage of the menstrual cycle compared to men at rest [46] and, therefore, the magnitude of the increase with resistance exercise appears to be less for the 22-kD response than men due to this higher starting concentration [29].

The isoform that is most common and measured in most studies using radioassay techniques is the 191 amino acid (22 kD) that is created by the cell’s genetic machinery. Thus, almost all studies examining the so-called GH have studied only the 22-kD monomer, and as a result, the process of its stimulation and secretion is well understood [46]. In response to a resistance training stimulus, growth-hormone-releasing hormone (GHRH) is secreted from the hypothalamus. GHRH travels along a network of blood vessels known as the hypophyseal portal system to the anterior pituitary where it meets its receptor. GH is then released from cells known as somatotroph cells, where it is produced. The external receptors are two GH-binding proteins followed by mediation with integral membrane receptors and then secondary signaling systems that follow for influence on the DNA in the nuclei. While an increase may occur in GHBP, no differences have been seen in men as to the effects of resistance training on the acute or chronic responses [48].

Increases of the 22 kD in circulation have been observed classically if the amount of muscle mass is great enough and, more importantly, if the metabolic needs for glycolysis are great [3, 16]. The 22 kD is very sensitive to changes in pH as reflected by high concentration of lactate in the blood [49]. Thus, short rest protocols which challenge the acid-base/pH status of the body will see more dramatic 22 kD increases in circulating concentrations [25, 26]. Conversely, various aggregates and binding proteins are less responsive to acute resistance exercise but resting concentrations are more responsive as a total change in GH molecules (all forms of GH including aggregates) [47, 50]. Measurement by bioassay is needed to mark such changes [45].

With acute resistance exercise (6 sets of 10 RM, 2-min rest between sets), no differences were observed for the tibial line bioassay examining the role of oral contraceptive (OC) use on GH aggregates and the 22 kD GH isoform [51]. The use of OC (OrthoTri-Cyclen™, 0.035 mg ethinyl estradiol and 0.180–0.250 mg norgestimate) augmented immunological GH response to the resistance exercise protocol in unfractionated plasma and > 60 kD molecular weight subfraction. However, OC use only increased biological activity of GH in one of the two bioassays. Thus, how the use of OC impacts the anterior pituitary release of GHs is both differential and novel, showing the future need for the effects of other OC combinations.

When in circulation, GH can exhibit its pleiotropic effects, playing important roles in fat metabolism , growth, reproduction, and immune and neural function. In the context of resistance training, GH also plays an important role in muscle development, both independent of insulin-like growth factor-I (IGF-I), such as in muscle cell fusion [52], and also as the old classic “somatomedin hypothesis” suggests, GH effects are mediated by circulating or locally produced IGF [52]. However, GH and its many variants and aggregates can influence cellular adaptations directly without help from the IGF superfamily [53].

The signal for the release of circulating IGF-I begins at the pituitary with secretion of what is believed to be the 22-kD GH monomer which is followed by a release of IGF-I from the liver [53]. Due to the structural similarity, much of the early research into IGF-I compared its metabolic effects with insulin, such as stimulation of protein metabolism , glucose transport, and glycogen and triglyceride synthesis, which explains how this group of factors acquired their name. IGFs are part of a sophisticated system sometimes referred to as the IGF axis that includes ligands such as IGF-I and IGF-II, receptors (e.g., IGF-I receptor (IGFIR) and IGF2R), many binding proteins (IGFBP1-6), as well as splice variants (IGF-IEa and IGF-IEc, also known as mechano growth factor (MGF)).

IGF-I is a 7.6-kD polypeptide consisting of 70 amino acids. IGF-I may also be a very important biomarker for health, fitness, and well-being [54]. After the early comparisons with insulin, more recent research has identified IGF-I as the signal molecule for two essential intracellular cascades: mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). IGF-II appears to play more of a role in embryogenesis [55]. Interestingly, IGF-I has shown variable responsiveness to resistance exercise, and the starting concentrations appear to be a major determinant if increases with exercise stress are observed and changes in acute recovery are variable [26, 29, 48]. With training, increases in resting concentrations occur, showing the importance of resting IGF-I cybernetics with physiological homeostasis [48].

When in circulation, IGF-I is complexed with one of the six binding proteins. These binding proteins are thought to play a role in transporting IGF-I to the target tissue [54]. There is evidence to suggest that the changes in binding proteins within the context of exercise models are a crucial aspect of modulating IGF-I bioactivity [56–58], and that it is not the amount of IGF-I that is important but the manner in which it is partitioned among its binding proteins [58]. Again, training did not appear to impact the acute response to heavy resistance exercise in men [48].

Again, in a very similar fashion to the insulin receptor, the IGF1R contains two extracellular alpha subunits and two transmembrane beta subunits. IGF-I binds to the alpha subunits, which induces an autophosphorylation of the beta subunit. The transmission of the signal that results in the downstream signaling of the MAPK or PI3K cascades is then determined by interactions involving insulin receptor substrate 1 (IRS-I) [53]. The MAPK cascade is primarily responsible for the proliferation of muscle cells. This occurs by changes in the amount and activity of transcription factors, such as increasing the expression of cyclins D1 and D2 which accelerates cell cycle progression [59]. The mitogenic activity of this pathway occurs essentially through the phosphorylation of ERK, half of which allows cell proliferation [60].

The PI3K cascade primarily mediates cell differentiation. PI3K signaling has three crucial roles: fusion of myoblasts into myotubes, anabolic effects on protein, and glucose uptake and resistance to apoptosis [61].

More recent research regarding IGF-I have shown that in response to mechanical stimuli, an alternative splicing of IGF-I occurs. It has been suggested that this splicing event results in the production of an mRNA species that is translated into a precursor that ultimately results in a peptide that is different from the typical IGF-I peptide. This peptide has been named the IGF-IEb (in rodents) or IGF-IEc (in humans) splice variant, and also MGF due to its expression after mechanical damage. Briefly, the hypothesis for the role of MGF is that after injury or mechanical stress, it activates satellite cells and plays a role in myoblast proliferation. Yet, as MGF inhibits differentiation, concentrations of MGF decrease and another splice variant, IGF-IEa, is able to potentiate differentiation. However, this is a new area of research and recent publications have questioned the amount of support for this theory [62]. Despite the fact that many questions regarding MGF remain, it is already being used as an ergogenic aid and being sold on the black market [63].

The impacts of resistance exercise on the reproductive hormonal axis are important beyond the aspects of reproductive biology and influence other hypopituitary and adrenal pathways as well. The many roles it plays in anabolic and catabolic signaling are just starting to be elucidated. Again, it must be remembered that hormones are only part of a very complex signaling system in the body and this system has dramatic redundancy. When considering the responses that occur as a result of resistance training, there are certain aspects of the stimulus that must first be understood, beginning with the size principle. If anabolic hormonal responses are going to occur beyond normal homeostatic maintenance of the cell, muscle fibers, they must first be recruited as part of motor unit activation in response to an exercise demand for force and power. In addition, it is possible that not only will unrecruited tissues not adapt, but may still be susceptible to damaging processes that occur as a result of reactive oxygen species or glucocorticoid exposure. If resistance training is successful in recruiting muscle fibers, hormonal responses will be governed by the upper regulatory elements as well as the manipulation of the acute program variables [14]. There are a variety of hormones and growth factors that may be secreted to induce adaptation of muscle tissue, with each doing so via its own mechanism of action of which some have been described. However, these mechanisms often impact each other, with complex interactions. This underscores the importance of an appreciation of the “big picture” when it comes to resistance training endocrinology and its interface with other physiological systems related to reproductive biology and exercise.

In a single endurance/aerobic exercise session, there are several components that dictate the magnitude and direction of the hormonal response. The key components of a single session are the intensity at which the exercise is performed and the duration of the exercise session [64–66]. Typically, the greater the intensity of exercise is, the greater is the degree of stress placed on the endocrine system and the more exacerbated the hormonal response becomes, that is, there are larger disturbances in the circulating hormonal concentrations [64, 65, 67]. It is important to recognize that in endurance exercises some hormones have intensity thresholds which need to be reached before a discernible change in the hormonal concentration of the blood can be noted. The major examples of this phenomenon are cortisol and GH, which respond once an intensity of 50–60 % VO_2max is reached. The direction of the responses in the circulating hormonal concentrations is varied, principally increased, but decreases can also occur [68]. Relative to duration, typically extending the length of time of an exercise session at any given intensity tends to amplify a hormone response. However, in some situations after the initial change in the hormonal concentration with exercise, there can be a plateau (i.e., steady state) of the response even as exercise duration is extended, or even possibly to some degree a decrease occurs [68, 69]

In addition to the intensity–duration components that can influence the hormonal response to an endurance exercise session, there are several other factors that can modify the response, such as environmental conditions, age, gender, nutrition status, circadian rhythms, genetics, and level of exercise training status. Space limitations do not allow for a discussion of these components here, but the readers are directed to several select references that address them in detail [66, 69].