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J Appl Physiol 122: 549558, 2017.

First published November 23, 2016; doi:10.1152/japplphysiol.00599.2016.

REVIEW Recovery from Exercise

Recovery responses of testosterone, growth hormone, and IGF-1 after


resistance exercise
William J. Kraemer,1 Nicholas A. Ratamess,2 and Bradley C. Nindl3
1
Department of Human Sciences, The Ohio State University, Columbus, Ohio; 2Department of Health and Exercise Science,
The College of New Jersey, Ewing, New Jersey; and 3Department of Sports Medicine and Nutrition, University of Pittsburgh,
Pittsburgh, Pennsylvania
Submitted 5 July 2016; accepted in final form 8 November 2016

Kraemer WJ, Ratamess NA, Nindl BC. Recovery responses of testosterone,


growth hormone, and IGF-1 after resistance exercise. J Appl Physiol 122: 549 558,
2017. First published November 23, 2016; doi:10.1152/japplphysiol.00599.2016.

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The complexity and redundancy of the endocrine pathways during recovery related
to anabolic function in the body belie an oversimplistic approach to its study. The
purpose of this review is to examine the role of resistance exercise (RE) on the
recovery responses of three major anabolic hormones, testosterone, growth hor-
mone(s), and insulin-like growth factor 1. Each hormone has a complexity related
to differential pathways of action as well as interactions with binding proteins and
receptor interactions. Testosterone is the primary anabolic hormone, and its con-
centration changes during the recovery period depending on the upregulation or
downregulation of the androgen receptor. Multiple tissues beyond skeletal muscle
are targeted under hormonal control and play critical roles in metabolism and
physiological function. Growth hormone (GH) demonstrates differential increases
in recovery with RE based on the type of GH being assayed and workout being
used. IGF-1 shows variable increases in recovery with RE and is intimately linked
to a host of binding proteins that are essential to its integrative actions and
mediating targeting effects. The RE stress is related to recruitment of muscle tissue
with the glandular release of hormones as signals to target tissues to support
homeostatic mechanisms for metabolism and tissue repair during the recovery
process. Anabolic hormones play a crucial role in the bodys response to metabo-
lism, repair, and adaptive capabilities especially in response to anabolic-type RE.
Changes of these hormones following RE during recovery in the circulatory
biocompartment of blood are reflective of the many mechanisms of action that are
in play in the repair and recovery process.
anabolic hormones; humans; muscle; strength training

RECOVERY MAY BE DEFINED as a return to normal homeostasis and other signal (e.g., growth factors and cytokines) interac-
following a transient disturbance. Exercise is a primary stim- tions, and the synthesis of new proteins. Thus recovery from
ulus disrupting homeostasis potentially leading to improve- RE requires an integrated response from several physiological
ments in various facets of performance. In particular, resistance systems. The inflammatory process involves the immune sys-
exercise (RE) is a potent stimulus resulting in acute muscle tem, which is highly influenced by the endocrine system.
fatigue that may persist for several hours to days following a Hormone signals play a variety of roles in anabolism (tissue
workout. Mechanical strain and subsequent skeletal muscle growth, substrate restoration, and recovery) and catabolism
damage resulting from RE of sufficient volume and intensity (tissue breakdown and metabolic regulation). The endocrine
produce structural disruptions of the contractile elements system supports the normal homeostatic function of the body
within activated muscle fibers. The outcomes from such events and assists in the responses and adaptations to external stimuli.
may be delayed onset muscle soreness or impaired physical Hormonal mechanisms are part of a complex integrated sig-
performance for up to several days. Muscle remodeling in- naling system that mediates changes in the metabolic and
volves the disruption and damage of muscle fibers, an inflam- cellular processes of skeletal muscle and neural and connective
matory response, degradation of damaged proteins, hormonal tissue as a function of training. However, hormones do not
function within a vacuum or isolated setting. Rather, a
Address for reprint requests and other correspondence: W. J. Kraemer, Dept.
specific hormonal response and adaptation must be viewed
of Human Sciences, A054 PAES Bldg., The Ohio State Univ., 305 Annie & within the context of the entire endocrine system and its
John Glenn Ave., Columbus, OH 43210 (e-mail: kraemer.44@osu.edu). relationship with other physiological systems.
http://www.jappl.org 8750-7587/17 Copyright 2017 the American Physiological Society 549
550 Hormones and Resistance Exercise Kraemer WJ et al.

Discussion of recovery involves close examination of the hormone (GnRH) stimulates the release of luteinizing hormone
quantity of force and power decrements, neural deficits, sub- from gonadotrophs. Other sources of testosterone synthesis
strate depletion, and muscle damage induced by the RE stim- include the zona reticularis of the adrenal cortex, ovaries, and
ulus and the subsequent postexercise physiological responses skeletal muscle (74, 75, 87). Testosterone is released into
that occur over the next 48 72 h. Acute hormonal responses circulation and transported mostly by sex hormone-binding
during RE, interaction with receptors and binding proteins, globulin (SHBG; 44 60%) and loosely bound to albumin or
receptor content, and the secretory patterns observed during other proteins. Free (unbound, up to 2% in circulation) testos-
subsequent days are critical, in part, to mediating recovery terone is taken up by tissues for binding to ARs and mediation
processes (see Fig. 1). The extent of the endocrine response is of recovery processes. SHBG concentrations influence the
dictated by the amount of muscle tissue activated, metabolic binding capacity of testosterone and the magnitude of free
demands of exercise, and recovery demands related to repair testosterone available for diffusion across the cell membrane.
and remodeling. The whole cascade of physiological events Steroidogenic enzyme content and testosterone concentrations
depends on the activation of motor units based on the size in skeletal muscle are similar between men and women (87)
principle, which, in turn, dictates the physiological system and have been shown to increase post-RE in older men (75) but
responses during recovery. A RE program is a composite of not in resistance-trained young men and women (87).
acute variables that can be manipulated to alter the stimulus Recovery from RE involves several mechanisms that replen-
and subsequently elicit specific adaptations (70). The key ish metabolic substrates, remove wastes and buffer acids,
qualities are that the exercise stimulus must surpass the indi- repair damaged tissues, and restore neuromuscular function.

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viduals threshold of adaptations, be specific to training goals, Several of these mechanisms, in part, are mediated by testos-
and be progressively overloaded and varied over time (70). terone and other androgens. Recovery enhancement via testos-
Thus hormones help prepare the body for RE and mediate terone not only may take place via endogenous responses to RE
recovery and long-term adaptations leading to enhanced per- but also has been shown during periods of exogenous androgen
formance. The purpose of this brief review is to discuss three administration (33). Testosterone induces anabolic and anti-
prominent hormones affecting recovery from RE: testosterone, catabolic mechanisms involved in muscle tissue growth, recov-
the growth hormone superfamily, and insulin-like growth fac- ery and remodeling, and performance enhancement. However,
tor 1. Specific hormonal responses to RE have been extensively the beneficial effects are not limited to skeletal muscle. Tes-
reviewed (50, 89). Here, a brief paradigm is presented linking tosterone stimulates the development of bone and other con-
testosterone, growth hormone, and IGF-1 to recovery and nective tissues and neural tissue (i.e., testosterone can interact
adaptations to training. with receptors on neurons and increase the amount of neu-
rotransmitters released, regenerate nerves, and increase cell
Testosterone and Other Androgens
body size and dendrite length/diameter) and induces erythro-
Testosterone is the primary androgen that interacts with poiesis (33).
androgen receptors (AR) within skeletal muscle whereas the Androgens have been shown to increase muscle cross-
more potent dihydrotestosterone primarily acts within sex- sectional area (CSA) of type I and II muscle fibers, muscle
linked tissues with secondary role in skeletal muscle (89). strength, power, and endurance (33). Testosterone administra-
Testosterone is synthesized from cholesterol in the Leydig cells tion has been shown to increase glucose transport via upregu-
of the testes (in men) under control of the hypothalamic- lated GLUT4 expression, augment insulin signaling via in-
anterior pituitary-gonadal axis where gonadotropin releasing creased insulin receptor substrate 1 and 2 (IRS1 and IRS2)

Exercise Stress the


interaction of intensity,
volume, rest interval
Amount of hormones & length, muscle mass Plasma volume shifts &
isoforms synthesized & involvement, muscle changes in tissue blood flow
stored actions, & motor units
recruited
Age & gender Training status
& body fat

Acute Blood Testosterone, GH,


Fig. 1. Factors that have been shown to influence the acute Release hormone IGF-1 Elevations & Receptor Nutritional
blood responses of testosterone, GH, and IGF-1 to RE and the
responses Up-regulation During Recovery intake &
postexercise recovery pattern of receptor upregulation.
From Resistance Exercise hydration

Time of day Genetics

Hormone metabolism,
Acidosis & hypoxia
clearance , & receptor
interaction
Quantity & conveyance of
transport proteins

J Appl Physiol doi:10.1152/japplphysiol.00599.2016 www.jappl.org


Hormones and Resistance Exercise Kraemer WJ et al. 551
expression, and increase glycogen synthesis via increased gly- tional (carbohydrate, protein, and L-carnitine) consumption
cogen synthase activity in skeletal muscle (41). Androgens before and after RE (35, 51).
have been shown to increase protein synthesis (94); alter fiber Androgen receptor content appears to not change or be
types (16); increase lactate transport via upregulation of mono- downregulated within the first 60 120 min of recovery follow-
carboxylate transporter 1 (MCT1) and 4 (MCT4) protein ex- ing RE in men (1, 51, 71, 82, 88) and 10 min of recovery in
pression (19); and increase satellite cell activation, prolifera- women (88), presumably because of the catabolic nature of
tion, mobilization, differentiation, and incorporation into skel- exercise. At 3-h post-RE, downregulation (in the absence of
etal muscle (10). In addition, androgens have been shown to nutrient consumption) may still persist following low-volume
increase myogenic marker upregulation, e.g., MyoD (56, 81), RE, but upregulation may occur following RE of higher vol-
differentiation of mesenchymal pluripotent cells and their com- ume that elicits a significant acute testosterone elevation during
mitment to myogenesis (81), follistatin expression (10, 56), exercise (82). Spillane et al. (83) reported significant upregu-
myotube formation (77), and myonuclear accretion and posi- lation of AR protein and AR-DNA binding at 3-h post-RE
tioning (40). Androgens may increase growth hormone (GH; (with a larger increase seen in a total body workout vs. lower
53), muscle IGF-1 isoform mRNA, e.g., mechano-growth fac- body); however, downregulation occurred at 24-h post-RE. A
tor and IGF-1Ea (56, 77), and Akt/4 mammalian target of lack of change in AR content has also been shown at 4- and
rapamycin (mTOR) pathway activation (7, 94); downregulate 24-h post-RE (53). At 48-h post-RE, AR content has been
and upregulate myostatin gene expression (10, 16); downregu- shown to not be different from resting content (1, 2) or be
late Acvr2b receptor mRNA (16); inhibit forkhead box O upregulated (6, 35). Given the complexities involved in andro-

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(FoxO) family of transcription factors catabolism (94); and gen-AR signaling, a firm time line of postexercise recovery AR
downregulate glucocorticoid receptor expression (56). Com- expression appears difficult to develop considering that differ-
petitive binding of androgens with glucocorticoid receptors and ences in study methodology, subject training status, nutritional
interference of glucocorticoid receptor transcriptional activity consumption, acute exercise stimuli, and limitations to sam-
via androgen/AR interaction have also been proposed mecha- pling points (i.e., 13 biopsies over a 48-h period) exist. In
nisms of androgen anticatabolism (12). general, the literature appears to suggest the initial AR re-
Androgens exert their actions through classic genomic sig- sponse may be no change or catabolic downregulation (if the
naling via bound androgen/AR complexes in the cytoplasm stimulus is of sufficient volume and intensity) followed by a
translocating to the nucleus to bind to specific androgen re- transient period of upregulation post-RE (1, 51, 71, 82, 88).
sponse elements of DNA, through genomic Wnt/-catenin The upregulation may be critical for mediating androgen-
signaling via Wnt-induced inhibition of glycogen synthase induced signaling of augmented protein synthesis or reduced
kinase 3 and subsequent -catenin translocation to the nucleus protein breakdown during recovery.
(80), and through rapid (seconds to minutes) nongenomic The recovery period following RE is influenced by the transient
actions involving binding to a cell surface AR or SHBG acute exercise-related elevations in anabolic hormones and sub-
receptor (linked to a G protein) leading to an increase in sequent return to normal diurnal secretory patterns. Acute RE
intracellular calcium (32). Although most studies have ex- elevates endogenous testosterone concentrations (50), which is
amined androgen-AR interaction via cytoplasmic receptor thought to increase the probability of testosterone-AR interac-
binding and nuclear translocation, recent evidence has tions. Serum concentrations of free testosterone have been
shown Wnt/-catenin signaling pathway is stimulated in shown to correlate to AR gene expression (72) thereby show-
response to total body RE with or without the presence of ing a relationship between circulating androgens and AR ex-
elevated androgens (83). pression in skeletal muscle. Some studies have shown relation-
Androgen receptors in tissues mediate the effects of andro- ships between exercise-induced testosterone and free testoster-
gens, which are typically stimulated in the recovery phase of a one elevations and AR content within 1 h of recovery
workout, and their expression depends on muscle fiber type, following RE (35) and 48-h post-RE (95). Spiering et al. (82)
contractile activity, and the concentrations of androgens (11, have shown that only a RE program that elicited significant
82). Changes in AR content determine receptor availability testosterone elevations resulted in AR upregulation at 3-h
and, ultimately, the net effects of androgens on target tissues postexercise. However, Kvorning et al. (53) reported no dif-
during recovery. The importance of androgens in mediating, in ferences in AR mRNA at 4- and 24-h post-RE where endog-
part, hypertrophic adaptations to training was shown in rats enous testosterone was elevated compared with a group with
where administration of an AR antagonist (oxendolone) atten- suppressed testosterone due to goserelin administration. In
uated 70% of the stimulation-induced hypertrophy compared contrast, some reports have shown no such relationship be-
with a control group (37) and in human studies where admin- tween acute or baseline testosterone and free testosterone and
istration of the GnRH analog goserelin completely attenuated AR mRNA and protein expression (1, 2). Basal AR protein
strength gains and partially attenuated lean tissue mass gains content and mRNA may not differ (1) or may be higher (72) in
following 8 wk of resistance training (RT; 52). Changes in AR older vs. young men. Baseline AR protein content or mRNA
protein content have been shown to correlate with relative may not change significantly at rest over long-term RT (8 wk
changes in muscle CSA (1) and maximal muscle strength to 12 mo; 1, 53) thereby suggesting that the cyclical upregu-
during and following RT (1, 71). Single and sequential bouts of lation and downregulation of AR content in response to se-
RE may increase AR protein expression or AR mRNA (6, quential RE bouts may be the most critical element to medi-
39, 95). The magnitude and time course of AR regulation ating androgen-induced muscular adaptations during recovery.
appear to be mediated by the volume of exercise (71), Resting testosterone concentrations have been used to mon-
muscle mass involvement (82, 83), and the quantity of itor recovery and subsequent adaptations to RT. Most studies
circulating testosterone in the blood (82), as well as nutri- have shown no changes in resting testosterone or free testos-

J Appl Physiol doi:10.1152/japplphysiol.00599.2016 www.jappl.org


552 Hormones and Resistance Exercise Kraemer WJ et al.

terone following a period of several weeks to months of RT and still not fully understood and has been the focus of many
(13, 52), although elevations (28) and reductions (69) have studies ranging from growth to tumor biology (22, 55, 68, 78).
also been shown. Ahtiainen et al. (1) reported no changes in Thus the concentrations of GH in the blood are related to the
resting testosterone concentrations (or AR protein and mRNA) specific assay (e.g., bioassay vs. immunoassay) used in the
at 24- and 48-h post-RE despite significant reductions in study.
maximal isometric force and elevations in serum creatine The release of GH from the anterior pituitary gland during
kinase and subjective muscle soreness. Other studies have recovery involves a multitude of molecular weight isoforms,
shown similar results (23). Because diurnal testosterone con- most notably, GH aggregates, which make up the highest assay
centrations are tightly regulated, it is unlikely for resting values signal or concentration in human plasma and are called bioas-
to chronically change as regulatory mechanisms are quickly sayable or bioactive GH (bGH; 36, 90). The concentrations of
reengaged during recovery. This was shown by Kraemer et al. GH in the blood during recovery are dependent on the exercise
(47), who reported that RE did not affect circadian patterns stimuli and the contents of GH contained in the somatotroph
over a 16-h period. However, McMurray et al. (60) did report cells of the anterior pituitary [i.e., either lower- (band 1) or
an elevated nocturnal testosterone response when RE was higher-molecular weight (band 2) isoforms] (20, 43). Never-
performed in the evening. Thus an augmentation of the testos- theless, little is known about how exercise stress alters soma-
terone response may be viewed as positive for enhancing totroph contents, function, and GH release into the blood
recovery because of greater circulating testosterone and poten- during recovery.
tial for tissue uptake and receptor binding. However, the The magnitude of the tropic stimulation of the anterior

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potential augmentation may only be transient before rapid pituitary gland from adrenocorticotropic hormone results in
return to homeostatic control. higher immunoreactive GH (iGH) responses, which peak ~15
The acute testosterone and androgen recovery responses to min into recovery (46, 54). It also appears that iGH is primarily
RE have been extensively reviewed (50, 89). Most studies have stimulated by anaerobic conditions (e.g., decreased pH and
shown significant elevations in recovery of testosterone and increased H; 25, 44, 48). In RE workouts this is characterized
free testosterone in men through 30 min into recovery (3, 4, 34, by short rest periods between sets and exercises, which stim-
46). In women, studies have shown no (27) or limited acute ulates higher concentrations of the iGH in the blood during
elevations (62). The magnitude of the acute responses in the recovery in both men and women. When longer rest is allowed
recovery period is affected by a host of different factors: because of the use of heavier resistances, the iGH responses in
exercise selection, intensity, volume, rest interval length, nu- recovery are significantly lower (44, 48). It has been speculated
tritional intake, and training experience (3, 4, 45, 48, 71, 82). that the higher iGH response is due to the inability to aggregate
Elevations in testosterone are attributed to plasma volume GH monomers in band 2 somatotrophs (due to inhibition of
reductions, adrenergic stimulation, reduced clearance, lactate- heat shock proteins and unstable chaperone proteins needed for
stimulated secretion, and increased synthesis and/or secretory aggregation; 43). Total work also plays a role with greater
capacity of androgen-producing tissues (50). The ramifications elevations in iGH as work increases (36, 48). In women, the
of acute elevations during RE are unclear. Considering that magnitude of change in iGH during recovery is typically less
diurnal hormonal concentrations are reengaged within 30 min compared with higher values obtained during the follicular
of recovery, the acute response may, in part, assist in governing phase of the menstrual cycle (45).
the recovery processes. In fact, some reports indicate relation- Important to the recovery processes involving GH is the fact
ships between testosterone elevation and AR upregulation and that two GH-binding proteins exist [i.e., high-affinity and
strength and hypertrophy enhancement (3, 4, 30, 82) whereas low-affinity GH-binding proteins (GHBP)] in circulation (67).
other reports indicate no such relationships (93). These con- The high-affinity GHBP results in the proteolytic cleavage of
flicting results demonstrate the complexity of hormonal re- the GH receptors extracellular domain, which can occur in the
sponses and the likelihood that several factors are contributing liver (as it has the most GH receptors) and any tissue with GH
to the response. Thus acute testosterone recovery responses receptors. Examining the high-affinity GHBP, Rubin et al. (73)
must be viewed within the context of multiple skeletal muscle showed that a standard heavy RE protocol [i.e., 6 sets of
signaling pathway adaptations as well as how they coincide 10-repetition maximum (RM) squats with 2 min of rest be-
with other androgens, GH, IGF-1, insulin, and cortisol re- tween sets] did not alter the plasma concentration, nor did
sponses. training influence the magnitude of response for GHBP. How-
ever, trained men showed higher iGH and IGF-1 concentra-
Growth Hormone(s) Superfamily tions in the recovery period. It was concluded that factors other
than hepatocytes may have masked increases in GH receptor
The understanding of exercise recovery patterns of growth expression but appear to have little effect on the recovery
hormone (GH) in the plasma now resides in a newly emerging pattern of iGH.
complexity related to its multiple target tissues and multiple Our understanding of the recovery response patterns of bGH
receptor interactions (43). While chronicled for over 75 yr, the to RE is limited. Most of the data that exist surround some type
pursuit of our understanding of GH is far from complete. It of RE or long-term training. We do know that afferent neural
might be hypothesized that it is not the single 22-kDa monomer feedback when using small muscle groups has been shown to
that mediates all of GH actions but rather a superfamily of be important to observing bGH increases after exercise (58,
different molecular isoforms (e.g., 20 kDa, non-22 kDa, 44 59). The human bGH response and RE first was studied using
kDa, and 66 kDa) that mediate physiological actions during a bed rest model. McCall et al. (59), using only repeated
recovery in response to exercise stress (8, 9, 49, 90). The GH plantar flexion isometric muscle actions at 30 80% of maxi-
receptor is somewhat ubiquitous in various cells and tissues mal voluntary contraction, showed that exercise-induced in-

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Hormones and Resistance Exercise Kraemer WJ et al. 553
creases of bGH in recovery occurred before the bed rest much lower concentrations compared with bGH. The systems
protocol but reappeared only after recovery from bed rest complexity, which has been discovered over the past decade,
stress. makes for a fertile area of investigation. An integrated biolog-
However, bGH has not been shown to be very responsive to ical approach to linking various GH molecular forms to adap-
whole body RE protocols, with concentrations highly variable tive mechanisms and end point outcomes in target tissues such
and not significantly higher than resting concentrations as one as muscle and connective tissue remains an important area of
goes through a recovery period of up to 70 min. A seminal study. Some of the regulatory mechanisms for GH release in
study by Hymer et al. (36) examined a full array of GH assays the peripheral circulation may also be related to differential
to an acute RE protocol (i.e., 6 sets of 10 RM with 2 min of rest blood flow control out of the pituitary gland itself, which
between sets) in young women. First, increases in the iGH remains speculative at best and in need of further investigation.
were observed in immunoassays with the higher concentration Figure 2 shows the generalized plasma responses of the ana-
signals arising from the monoclonal assay compared with the bolic hormones discussed in this review during the recovery
polyclonal assay. However, the signal strength varied across period.
the molecular weight fractions of the plasma, with higher
signals for concentrations in the plasma lower-molecular Insulin-like Growth Factor 1 System
weight fraction as might be expected with immunoassays
targeting the 22-kDa isoform. Surprisingly, in the rat tibial line IGF-1 is an anabolic and metabolic hormone released by the
bioassay, no significant exercise-induced increases in the im- liver into the systemic circulation and also produced locally

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mediate postexercise recovery sample or in any of the molec- (i.e., autocrine and paracrine mechanisms) in tissues and cells
ular weight fractions occurred. Strikingly, as shown by McCall (57, 64). IGF-1 is under exquisite regulation by a family of
et al. (59) in men, the signals for concentrations arising from binding proteins (IGFBPs 1 6) (13), which are also released
the bioassay were dramatically higher (i.e., from ~1,000 to primarily by the liver and can either stimulate or inhibit IGF-1
2,300 g/l compared with ~515 g/l for bioassay vs. immu- biological action. The anabolic effects of IGF-1 involve acting
noassay, respectively). In a later acute study in young men, as both a cell cycle initiation and progression factor and center
again no acute exercise-induced increases in bGH were ob- on satellite cell activation, proliferation, survival, and differ-
served in response to RE using 3 sets of 10 RM (86). However, entiation (57). The metabolic effects of IGF-1 include stimu-
reflecting what has been seen in iGH (91), men who were lating protein synthesis, free fatty acid utilization, and enhanc-
classified as being overweight had significantly lower bGH ing insulin sensitivity (13, 21). While liver-derived IGF-1 is
concentrations. Interestingly, iGH significantly increased in under direct regulation of GH release from the anterior pitu-
both lean and obese groups in response to the RE protocol (86), itary, local mechanical-stretch mechanisms can also activate
yet in adolescents who were overweight and performing re- IGF-1 synthesis in local tissues. Many aspects of IGF-1 biol-
peated 2-min bouts of high-intensity cycle exercise the GH ogy (IGF-1 bioavailability, sequestration of IGF-1 across
response was attenuated (18). Thus it remains unclear why IGFBPs and biocompartments, IGF-1 receptor activation, etc.)
bGH is not seen to be elevated after exercise in the recovery all contribute to elicit a significant biological impact. The
period, and more study is needed to clarify such observations. influence of IGF-1 in mediating some of the beneficial aspects
Maybe with training the bGH might be more responsive to of exercise particularly with regard to postexercise recovery
a RE stress. This was one of the questions examined in an and remodeling mechanisms for muscle tissue has been an area
intensive 6-mo RT study in women (49). Using a 6 times of intense interest (64, 84).
10-RM squat exercise protocol, no acute increases were ob- Early cross-sectional reports of an association between cir-
served pretraining in bGH, while increases were again classi- culating IGF-1 and aerobic fitness suggested that IGF-1 could
cally demonstrated in the iGH assays. However, with training perhaps be considered a biomarker of health and fitness and an
the recovery responses of bGH were still not affected. It was important mediator of exercise outcomes (17, 64, 65). In a
discovered that resting bGH values responded with significant 2011 study that examined circulating IGF-1 and fitness out-
elevations primarily in larger plasma fractions (30 kDa). comes in 846 Finnish soldiers, circulating IGF-1 was associ-
Concomitantly, expected increases in iGH were seen with ated with higher levels of aerobic fitness and muscular endur-
acute exercise with higher concentrations during the postexer- ance, but not with muscle strength or fat-free mass (65). Even
cise recovery period posttraining. Thus bGH elevation appears given the anabolic actions of IGF-1, a direct link between
insensitive to acute RE stress. However, bGH is expressed in a exercise-induced increases in circulating IGF-1 and subsequent
higher resting concentration indicating it may be a reservoir of anabolism for muscle hypertrophy and strength has been dif-
GH molecules. What factors contribute to individual variation ficult to experimentally determine (31). From a 2010 Point-
in bGH in response to exercise of different types in men and Counterpoint on whether IGF-1 was the major regulator of
women needs extensive study. Recently, lower recovery con- muscle mass, the ability of IGF-1 to promote muscle hyper-
centrations of bGH have been observed in older women (~60 trophy went unchallenged, but as there is strong evidence that
yr) compared with younger women (~30 yr), lending some muscle remodeling is mostly attributed to mechanical strength
support to the idea that aging in both iGH and bGH is in some and overload, the role of IGF-1 may lie more in being a
way affected by glandular cellular apoptosis (24). regulator or amplifier of muscle remodeling (84). While
The anterior pituitary glands function and the release of GH West et al. (92) have reported data suggesting similar muscle
are far from understood as to its release and restoration of GH anabolic responses to RT under high- or low-GH/IGF environ-
isoforms, splice variants, and aggregates back to resting ho- ments, other data indicate a stimulatory effect of IGF-1 on
meostatic concentrations. It appears that the more rapid re- satellite cell activation and muscle regeneration (14, 15, 31).
sponse patterns are related to the 22-kDa iGH isoform but in However, because of the regulatory complexity governing the

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554 Hormones and Resistance Exercise Kraemer WJ et al.

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Fig. 2. General plasma response patterns in the fasted state of testosterone, bioactive growth (bGH), immunoreactive growth hormone (iGH), and insulin-like
growth factor 1 (IGF-1) to RE are presented. Testosterone and iGH typically increase with RE within the first 1530 min and then return to resting concentrations
within the hour. bGH typically increases or remains the same throughout the recovery time frame at values much higher than iGH. More variability is observed
with IGF-1 with increases or decreases observed into recovery while values return to resting concentrations within 12 h. IP, immediately postexercise.

IGF-1 system, more research is required to fully understand the demands (13, 38). For example, Bajer et al. (5) have recently
precise role IGF-1 has in mediating postexercise recovery (64). written about IGF-1 as a powerful determinant of exercise-
Lending more confusion to understanding the IGF-1 re- associated fat mass loss.
sponse and role in postexercise recovery mechanisms are In an effort to gain greater insight into the IGF-1 response to
conflicting reports in the literature of IGF-1 increases, de- exercise, studies have also been conducted utilizing microdi-
creases, and no change (26, 42, 61, 64). As a pleiotropic alysis to measure IGF-1 in interstitial fluid (ISF; the fluid
hormone, it is possible that IGF-1 may be a regulator and/or bathing muscle tissue; 66). ISF remains a relatively unexplored
amplifier for some overall metabolic influences mediating biocompartment that could provide meaningful signature clues
exercise-induced responses that are contextual dependent (21, to the mechanotransduction of RE. In subjects who performed
84). One aspect of IGF-1 physiology that must be considered explosive, high-power exercise, total and free IGF-1 and
with regard to exercise responses is the response of IGFBPs IGFBP-3 were increased, whereas ISF IGF-1 was unaltered
(38). Of the studies reporting IGF-1 increases postexercise, this (ISF IGFBPs were not measured). Of notable interest in this
increase is only transient and returns to baseline within 10 30 study, the IGF-1 receptor phosphorylation was not increased,
min. The data for postexercise IGFBP responses are more and IGF mRNA content and Akt phosphorylation were in-
consistent (85). Monitoring overnight IGF-1 system concen- creased. These data reinforce the concept that skeletal muscle
trations following a bout of heavy RE, we have reported that remodeling and adaptation are not simply dependent on an
IGF-1 concentrations remained unchanged but that IGFBP-2 increase in circulating IGF-1, but rather the interplay between
was increased and acid-labile subunit was decreased (63). the IGF system across biocompartments and the mechanotrans-
These results suggested that the impact of exercise on the duction imposed by physical activity. In a recent unpublished
circulating IGF-1 system was not in alterations in the amount study from our laboratory where ISF IGFBPs were measured in
of IGF-1, but rather the manner in which IGF-1 is partitioned subjects performing unilateral stretch-shortening cycle exer-
among its family of binding proteins. In a randomized, control cises until exhaustion, localized and differential IGFBP re-
follow-up study in which subjects participated in both aerobic sponses were observed as IGFBP-3 and -5 were increased only
and RE bouts of differing durations (1 and 2 h), IGFBP-1 was in the exercised leg. In another application of microdialysis in
sensitive to exercise duration, but not exercise mode. IGFBP-1 understanding IGF-1 physiology and exercise, Hansen et al.
was increased over the control condition for the 2-h exercise (29) reported that oral contraceptive use resulted in lower
bouts (94). From a metabolic perspective, this is an important concentrations of circulating and ISF IGF-1 associated with
finding for the IGF-1 system as IGFBP-1 is known to have a lower postexercise collagen synthesis. Taken together, the
dynamic role in glucose/energy homeostasis. IGFBP-1 is available evidence points toward the importance of the meth-
known to be inversely proportional to insulin and to sequester odology used to discern the contributory and regulatory roles
free IGF-1. The exercise-induced increase for IGFBP-1 may be of the IGFBP response to postexercise recovery and metabolic
related to modulating IGF-1 bioactivity to match energy flux sequelae.

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Local muscle IGF-1 has consistently been shown to be 3. Ahtiainen JP, Pakarinen A, Alen M, Kraemer WJ, Hkkinen K.
upregulated with exercise. Using muscle biopsy and immuno- Muscle hypertrophy, hormonal adaptations and strength development
during strength training in strength-trained and untrained men. Eur J Appl
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DISCLOSURES emalie L, Spans L, Gayan-Ramirez G, Deldicque L, Hespel P, Car-
No conflicts of interest, financial or otherwise, are declared by the author(s). meliet G, Vanderschueren D, Claessens F. A satellite cell-specific
knockout of the androgen receptor reveals myostatin as a direct androgen
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AUTHOR CONTRIBUTIONS
14-249748.
W.J.K., N.A.R., and B.C.N. interpreted results of experiments; W.J.K., 17. Eliakim A, Brasel JA, Mohan S, Barstow TJ, Berman N, Cooper DM.
N.A.R., and B.C.N. prepared figures; W.J.K., N.A.R., and B.C.N. drafted Physical fitness, endurance training, and the growth hormone-insulin-like
manuscript; W.J.K., N.A.R., and B.C.N. edited and revised manuscript; growth factor I system in adolescent females. J Clin Endocrinol Metab 81:
W.J.K., N.A.R., and B.C.N. approved final version of manuscript. 3986 3992, 1996.
18. Eliakim A, Nemet D, Zaldivar F, McMurray RG, Culler FL, Galas-
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