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.

Downloaded from http://jap.physiology.org/ by 10.220.32.246 on March 11, 2017

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
following a transient disturbance. Exercise is a primary stim-
ulus disrupting homeostasis potentially leading to improve-
ments in various facets of performance. In particular, resistance
exercise (RE) is a potent stimulus resulting in acute muscle
fatigue that may persist for several hours to days following a
workout. Mechanical strain and subsequent skeletal muscle
damage resulting from RE of sufficient volume and intensity
produce structural disruptions of the contractile elements
within activated muscle fibers. The outcomes from such events
may be delayed onset muscle soreness or impaired physical
performance for up to several days. Muscle remodeling in-
volves the disruption and damage of muscle fibers, an inflam-
matory response, degradation of damaged proteins, hormonal
Address for reprint requests and other correspondence: W. J. Kraemer, Dept.
of Human Sciences, A054 PAES Bldg., The Ohio State Univ., 305 Annie &
John Glenn Ave., Columbus, OH 43210 (e-mail: kraemer.44@osu.edu).
http://www.jappl.org 8750-7587/17 Copyright 2017 the American Physiological Society
and other signal (e.g., growth factors and cytokines) interac-
tions, and the synthesis of new proteins. Thus recovery from
RE requires an integrated response from several physiological
systems. The inflammatory process involves the immune sys-
tem, which is highly influenced by the endocrine system.
Hormone signals play a variety of roles in anabolism (tissue
growth, substrate restoration, and recovery) and catabolism
(tissue breakdown and metabolic regulation). The endocrine
system supports the normal homeostatic function of the body
and assists in the responses and adaptations to external stimuli.
Hormonal mechanisms are part of a complex integrated sig-
naling system that mediates changes in the metabolic and
cellular processes of skeletal muscle and neural and connective
tissue as a function of training. However, hormones do not
function within a vacuum or isolated setting. Rather, a
specific hormonal response and adaptation must be viewed
within the context of the entire endocrine system and its
relationship with other physiological systems.
549
550 Hormones and Resistance Exercise Kraemer WJ et al.
Discussion of recovery involves close examination of the
quantity of force and power decrements, neural deficits, sub-
strate depletion, and muscle damage induced by the RE stim-
ulus and the subsequent postexercise physiological responses
that occur over the next 48 72 h. Acute hormonal responses
during RE, interaction with receptors and binding proteins,
receptor content, and the secretory patterns observed during
subsequent days are critical, in part, to mediating recovery
processes (see Fig. 1). The extent of the endocrine response is
dictated by the amount of muscle tissue activated, metabolic
demands of exercise, and recovery demands related to repair
and remodeling. The whole cascade of physiological events
depends on the activation of motor units based on the size
principle, which, in turn, dictates the physiological system
responses during recovery. A RE program is a composite of
acute variables that can be manipulated to alter the stimulus
and subsequently elicit specific adaptations (70). The key
qualities are that the exercise stimulus must surpass the indi-
viduals threshold of adaptations, be specific to training goals,
and be progressively overloaded and varied over time (70).
Thus hormones help prepare the body for RE and mediate
recovery and long-term adaptations leading to enhanced per-
formance. The purpose of this brief review is to discuss three
prominent hormones affecting recovery from RE: testosterone,
the growth hormone superfamily, and insulin-like growth fac-
tor 1. Specific hormonal responses to RE have been extensively
reviewed (50, 89). Here, a brief paradigm is presented linking
testosterone, growth hormone, and IGF-1 to recovery and
adaptations to training.
Testosterone and Other Androgens
Testosterone is the primary androgen that interacts with
androgen receptors (AR) within skeletal muscle whereas the
more potent dihydrotestosterone primarily acts within sex-
linked tissues with secondary role in skeletal muscle (89).
Testosterone is synthesized from cholesterol in the Leydig cells
of the testes (in men) under control of the hypothalamic-
anterior pituitary-gonadal axis where gonadotropin releasing
Fig. 1. Factors that have been shown to influence the acute
blood responses of testosterone, GH, and IGF-1 to RE and the
postexercise recovery pattern of receptor upregulation.
J Appl Physiol doi:10.1152/japplphysiol.00599.2016 www.jappl.org
hormone (GnRH) stimulates the release of luteinizing hormone
from gonadotrophs. Other sources of testosterone synthesis
include the zona reticularis of the adrenal cortex, ovaries, and
skeletal muscle (74, 75, 87). Testosterone is released into
circulation and transported mostly by sex hormone-binding
globulin (SHBG; 44 60%) and loosely bound to albumin or
other proteins. Free (unbound, up to 2% in circulation) testos-
terone is taken up by tissues for binding to ARs and mediation
of recovery processes. SHBG concentrations influence the
binding capacity of testosterone and the magnitude of free
testosterone available for diffusion across the cell membrane.
Steroidogenic enzyme content and testosterone concentrations
in skeletal muscle are similar between men and women (87)
and have been shown to increase post-RE in older men (75) but
not in resistance-trained young men and women (87).
Recovery from RE involves several mechanisms that replen-
ish metabolic substrates, remove wastes and buffer acids,
repair damaged tissues, and restore neuromuscular function.
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Several of these mechanisms, in part, are mediated by testos-
terone and other androgens. Recovery enhancement via testos-
terone not only may take place via endogenous responses to RE
but also has been shown during periods of exogenous androgen
administration (33). Testosterone induces anabolic and anti-
catabolic mechanisms involved in muscle tissue growth, recov-
ery and remodeling, and performance enhancement. However,
the beneficial effects are not limited to skeletal muscle. Tes-
tosterone stimulates the development of bone and other con-
nective tissues and neural tissue (i.e., testosterone can interact
with receptors on neurons and increase the amount of neu-
rotransmitters released, regenerate nerves, and increase cell
body size and dendrite length/diameter) and induces erythro-
poiesis (33).
Androgens have been shown to increase muscle cross-
sectional area (CSA) of type I and II muscle fibers, muscle
strength, power, and endurance (33). Testosterone administra-
tion has been shown to increase glucose transport via upregu-
lated GLUT4 expression, augment insulin signaling via in-
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,
Release hormone IGF-1 Elevations & Receptor Nutritional
responses Up-regulation During Recovery intake &
From Resistance Exercise hydration
Time of day Genetics
Hormone metabolism,
Acidosis & hypoxia
clearance , & receptor
interaction
Quantity & conveyance of
transport proteins
 Hormones and Resistance Exercise Kraemer WJ et al.
expression, and increase glycogen synthesis via increased gly-
cogen synthase activity in skeletal muscle (41). Androgens
have been shown to increase protein synthesis (94); alter fiber
types (16); increase lactate transport via upregulation of mono-
carboxylate transporter 1 (MCT1) and 4 (MCT4) protein ex-
pression (19); and increase satellite cell activation, prolifera-
tion, mobilization, differentiation, and incorporation into skel-
etal muscle (10). In addition, androgens have been shown to
increase myogenic marker upregulation, e.g., MyoD (56, 81),
differentiation of mesenchymal pluripotent cells and their com-
mitment to myogenesis (81), follistatin expression (10, 56),
myotube formation (77), and myonuclear accretion and posi-
tioning (40). Androgens may increase growth hormone (GH;
53), muscle IGF-1 isoform mRNA, e.g., mechano-growth fac-
tor and IGF-1Ea (56, 77), and Akt/4 mammalian target of
rapamycin (mTOR) pathway activation (7, 94); downregulate
and upregulate myostatin gene expression (10, 16); downregu-
late Acvr2b receptor mRNA (16); inhibit forkhead box O
(FoxO) family of transcription factors catabolism (94); and
downregulate glucocorticoid receptor expression (56). Com-
petitive binding of androgens with glucocorticoid receptors and
interference of glucocorticoid receptor transcriptional activity
via androgen/AR interaction have also been proposed mecha-
nisms of androgen anticatabolism (12).
Androgens exert their actions through classic genomic sig-
naling via bound androgen/AR complexes in the cytoplasm
translocating to the nucleus to bind to specific androgen re-
sponse elements of DNA, through genomic Wnt/-catenin
signaling via Wnt-induced inhibition of glycogen synthase
kinase 3 and subsequent -catenin translocation to the nucleus
(80), and through rapid (seconds to minutes) nongenomic
actions involving binding to a cell surface AR or SHBG
receptor (linked to a G protein) leading to an increase in
intracellular calcium (32). Although most studies have ex-
amined androgen-AR interaction via cytoplasmic receptor
binding and nuclear translocation, recent evidence has
shown Wnt/-catenin signaling pathway is stimulated in
response to total body RE with or without the presence of
elevated androgens (83).
Androgen receptors in tissues mediate the effects of andro-
gens, which are typically stimulated in the recovery phase of a
workout, and their expression depends on muscle fiber type,
contractile activity, and the concentrations of androgens (11,
82). Changes in AR content determine receptor availability
and, ultimately, the net effects of androgens on target tissues
during recovery. The importance of androgens in mediating, in
part, hypertrophic adaptations to training was shown in rats
where administration of an AR antagonist (oxendolone) atten-
uated 70% of the stimulation-induced hypertrophy compared
with a control group (37) and in human studies where admin-
istration of the GnRH analog goserelin completely attenuated
strength gains and partially attenuated lean tissue mass gains
following 8 wk of resistance training (RT; 52). Changes in AR
protein content have been shown to correlate with relative
changes in muscle CSA (1) and maximal muscle strength
during and following RT (1, 71). Single and sequential bouts of
RE may increase AR protein expression or AR mRNA (6,
39, 95). The magnitude and time course of AR regulation
appear to be mediated by the volume of exercise (71),
muscle mass involvement (82, 83), and the quantity of
circulating testosterone in the blood (82), as well as nutri-
J Appl Physiol doi:10.1152/japplphysiol.00599.2016 www.jappl.org
551
tional (carbohydrate, protein, and L-carnitine) consumption
before and after RE (35, 51).
Androgen receptor content appears to not change or be
downregulated within the first 60 120 min of recovery follow-
ing RE in men (1, 51, 71, 82, 88) and 10 min of recovery in
women (88), presumably because of the catabolic nature of
exercise. At 3-h post-RE, downregulation (in the absence of
nutrient consumption) may still persist following low-volume
RE, but upregulation may occur following RE of higher vol-
ume that elicits a significant acute testosterone elevation during
exercise (82). Spillane et al. (83) reported significant upregu-
lation of AR protein and AR-DNA binding at 3-h post-RE
(with a larger increase seen in a total body workout vs. lower
body); however, downregulation occurred at 24-h post-RE. A
lack of change in AR content has also been shown at 4- and
24-h post-RE (53). At 48-h post-RE, AR content has been
shown to not be different from resting content (1, 2) or be
upregulated (6, 35). Given the complexities involved in andro-
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gen-AR signaling, a firm time line of postexercise recovery AR
expression appears difficult to develop considering that differ-
ences in study methodology, subject training status, nutritional
consumption, acute exercise stimuli, and limitations to sam-
pling points (i.e., 13 biopsies over a 48-h period) exist. In
general, the literature appears to suggest the initial AR re-
sponse may be no change or catabolic downregulation (if the
stimulus is of sufficient volume and intensity) followed by a
transient period of upregulation post-RE (1, 51, 71, 82, 88).
The upregulation may be critical for mediating androgen-
induced signaling of augmented protein synthesis or reduced
protein breakdown during recovery.
The recovery period following RE is influenced by the transient
acute exercise-related elevations in anabolic hormones and sub-
sequent return to normal diurnal secretory patterns. Acute RE
elevates endogenous testosterone concentrations (50), which is
thought to increase the probability of testosterone-AR interac-
tions. Serum concentrations of free testosterone have been
shown to correlate to AR gene expression (72) thereby show-
ing a relationship between circulating androgens and AR ex-
pression in skeletal muscle. Some studies have shown relation-
ships between exercise-induced testosterone and free testoster-
one elevations and AR content within 1 h of recovery
following RE (35) and 48-h post-RE (95). Spiering et al. (82)
have shown that only a RE program that elicited significant
testosterone elevations resulted in AR upregulation at 3-h
postexercise. However, Kvorning et al. (53) reported no dif-
ferences in AR mRNA at 4- and 24-h post-RE where endog-
enous testosterone was elevated compared with a group with
suppressed testosterone due to goserelin administration. In
contrast, some reports have shown no such relationship be-
tween acute or baseline testosterone and free testosterone and
AR mRNA and protein expression (1, 2). Basal AR protein
content and mRNA may not differ (1) or may be higher (72) in
older vs. young men. Baseline AR protein content or mRNA
may not change significantly at rest over long-term RT (8 wk
to 12 mo; 1, 53) thereby suggesting that the cyclical upregu-
lation and downregulation of AR content in response to se-
quential RE bouts may be the most critical element to medi-
ating androgen-induced muscular adaptations during recovery.
Resting testosterone concentrations have been used to mon-
itor recovery and subsequent adaptations to RT. Most studies
have shown no changes in resting testosterone or free testos-
552 Hormones and Resistance Exercise Kraemer WJ et al.
terone following a period of several weeks to months of RT
(13, 52), although elevations (28) and reductions (69) have
also been shown. Ahtiainen et al. (1) reported no changes in
resting testosterone concentrations (or AR protein and mRNA)
at 24- and 48-h post-RE despite significant reductions in
maximal isometric force and elevations in serum creatine
kinase and subjective muscle soreness. Other studies have
shown similar results (23). Because diurnal testosterone con-
centrations are tightly regulated, it is unlikely for resting values
to chronically change as regulatory mechanisms are quickly
reengaged during recovery. This was shown by Kraemer et al.
(47), who reported that RE did not affect circadian patterns
over a 16-h period. However, McMurray et al. (60) did report
an elevated nocturnal testosterone response when RE was
performed in the evening. Thus an augmentation of the testos-
terone response may be viewed as positive for enhancing
recovery because of greater circulating testosterone and poten-
tial for tissue uptake and receptor binding. However, the
potential augmentation may only be transient before rapid
return to homeostatic control.
The acute testosterone and androgen recovery responses to
RE have been extensively reviewed (50, 89). Most studies have
shown significant elevations in recovery of testosterone and
free testosterone in men through 30 min into recovery (3, 4, 34,
46). In women, studies have shown no (27) or limited acute
elevations (62). The magnitude of the acute responses in the
recovery period is affected by a host of different factors:
exercise selection, intensity, volume, rest interval length, nu-
tritional intake, and training experience (3, 4, 45, 48, 71, 82).
Elevations in testosterone are attributed to plasma volume
reductions, adrenergic stimulation, reduced clearance, lactate-
stimulated secretion, and increased synthesis and/or secretory
capacity of androgen-producing tissues (50). The ramifications
of acute elevations during RE are unclear. Considering that
diurnal hormonal concentrations are reengaged within 30 min
of recovery, the acute response may, in part, assist in governing
the recovery processes. In fact, some reports indicate relation-
ships between testosterone elevation and AR upregulation and
strength and hypertrophy enhancement (3, 4, 30, 82) whereas
other reports indicate no such relationships (93). These con-
flicting results demonstrate the complexity of hormonal re-
sponses and the likelihood that several factors are contributing
to the response. Thus acute testosterone recovery responses
must be viewed within the context of multiple skeletal muscle
signaling pathway adaptations as well as how they coincide
with other androgens, GH, IGF-1, insulin, and cortisol re-
sponses.
Growth Hormone(s) Superfamily
The understanding of exercise recovery patterns of growth
hormone (GH) in the plasma now resides in a newly emerging
complexity related to its multiple target tissues and multiple
receptor interactions (43). While chronicled for over 75 yr, the
pursuit of our understanding of GH is far from complete. It
might be hypothesized that it is not the single 22-kDa monomer
that mediates all of GH actions but rather a superfamily of
different molecular isoforms (e.g., 20 kDa, non-22 kDa, 44
kDa, and 66 kDa) that mediate physiological actions during
recovery in response to exercise stress (8, 9, 49, 90). The GH
receptor is somewhat ubiquitous in various cells and tissues
J Appl Physiol doi:10.1152/japplphysiol.00599.2016 www.jappl.org
and still not fully understood and has been the focus of many
studies ranging from growth to tumor biology (22, 55, 68, 78).
Thus the concentrations of GH in the blood are related to the
specific assay (e.g., bioassay vs. immunoassay) used in the
study.
The release of GH from the anterior pituitary gland during
recovery involves a multitude of molecular weight isoforms,
most notably, GH aggregates, which make up the highest assay
signal or concentration in human plasma and are called bioas-
sayable or bioactive GH (bGH; 36, 90). The concentrations of
GH in the blood during recovery are dependent on the exercise
stimuli and the contents of GH contained in the somatotroph
cells of the anterior pituitary [i.e., either lower- (band 1) or
higher-molecular weight (band 2) isoforms] (20, 43). Never-
theless, little is known about how exercise stress alters soma-
totroph contents, function, and GH release into the blood
during recovery.
The magnitude of the tropic stimulation of the anterior
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pituitary gland from adrenocorticotropic hormone results in
higher immunoreactive GH (iGH) responses, which peak ~15
min into recovery (46, 54). It also appears that iGH is primarily
stimulated by anaerobic conditions (e.g., decreased pH and
increased H; 25, 44, 48). In RE workouts this is characterized
by short rest periods between sets and exercises, which stim-
ulates higher concentrations of the iGH in the blood during
recovery in both men and women. When longer rest is allowed
because of the use of heavier resistances, the iGH responses in
recovery are significantly lower (44, 48). It has been speculated
that the higher iGH response is due to the inability to aggregate
GH monomers in band 2 somatotrophs (due to inhibition of
heat shock proteins and unstable chaperone proteins needed for
aggregation; 43). Total work also plays a role with greater
elevations in iGH as work increases (36, 48). In women, the
magnitude of change in iGH during recovery is typically less
compared with higher values obtained during the follicular
phase of the menstrual cycle (45).
Important to the recovery processes involving GH is the fact
that two GH-binding proteins exist [i.e., high-affinity and
low-affinity GH-binding proteins (GHBP)] in circulation (67).
The high-affinity GHBP results in the proteolytic cleavage of
the GH receptors extracellular domain, which can occur in the
liver (as it has the most GH receptors) and any tissue with GH
receptors. Examining the high-affinity GHBP, Rubin et al. (73)
showed that a standard heavy RE protocol [i.e., 6 sets of
10-repetition maximum (RM) squats with 2 min of rest be-
tween sets] did not alter the plasma concentration, nor did
training influence the magnitude of response for GHBP. How-
ever, trained men showed higher iGH and IGF-1 concentra-
tions in the recovery period. It was concluded that factors other
than hepatocytes may have masked increases in GH receptor
expression but appear to have little effect on the recovery
pattern of iGH.
Our understanding of the recovery response patterns of bGH
to RE is limited. Most of the data that exist surround some type
of RE or long-term training. We do know that afferent neural
feedback when using small muscle groups has been shown to
be important to observing bGH increases after exercise (58,
59). The human bGH response and RE first was studied using
a bed rest model. McCall et al. (59), using only repeated
plantar flexion isometric muscle actions at 30 80% of maxi-
mal voluntary contraction, showed that exercise-induced in-
 Hormones and Resistance Exercise Kraemer WJ et al.
creases of bGH in recovery occurred before the bed rest
protocol but reappeared only after recovery from bed rest
stress.
However, bGH has not been shown to be very responsive to
whole body RE protocols, with concentrations highly variable
and not significantly higher than resting concentrations as one
goes through a recovery period of up to 70 min. A seminal
study by Hymer et al. (36) examined a full array of GH assays
to an acute RE protocol (i.e., 6 sets of 10 RM with 2 min of rest
between sets) in young women. First, increases in the iGH
were observed in immunoassays with the higher concentration
signals arising from the monoclonal assay compared with the
polyclonal assay. However, the signal strength varied across
the molecular weight fractions of the plasma, with higher
signals for concentrations in the plasma lower-molecular
weight fraction as might be expected with immunoassays
targeting the 22-kDa isoform. Surprisingly, in the rat tibial line
bioassay, no significant exercise-induced increases in the im-
mediate postexercise recovery sample or in any of the molec-
ular weight fractions occurred. Strikingly, as shown by McCall
et al. (59) in men, the signals for concentrations arising from
the bioassay were dramatically higher (i.e., from ~1,000 to
2,300 g/l compared with ~515 g/l for bioassay vs. immu-
noassay, respectively). In a later acute study in young men,
again no acute exercise-induced increases in bGH were ob-
served in response to RE using 3 sets of 10 RM (86). However,
reflecting what has been seen in iGH (91), men who were
classified as being overweight had significantly lower bGH
concentrations. Interestingly, iGH significantly increased in
both lean and obese groups in response to the RE protocol (86),
yet in adolescents who were overweight and performing re-
peated 2-min bouts of high-intensity cycle exercise the GH
response was attenuated (18). Thus it remains unclear why
bGH is not seen to be elevated after exercise in the recovery
period, and more study is needed to clarify such observations.
Maybe with training the bGH might be more responsive to
a RE stress. This was one of the questions examined in an
intensive 6-mo RT study in women (49). Using a 6 times
10-RM squat exercise protocol, no acute increases were ob-
served pretraining in bGH, while increases were again classi-
cally demonstrated in the iGH assays. However, with training
the recovery responses of bGH were still not affected. It was
discovered that resting bGH values responded with significant
elevations primarily in larger plasma fractions (30 kDa).
Concomitantly, expected increases in iGH were seen with
acute exercise with higher concentrations during the postexer-
cise recovery period posttraining. Thus bGH elevation appears
insensitive to acute RE stress. However, bGH is expressed in a
higher resting concentration indicating it may be a reservoir of
GH molecules. What factors contribute to individual variation
in bGH in response to exercise of different types in men and
women needs extensive study. Recently, lower recovery con-
centrations of bGH have been observed in older women (~60
yr) compared with younger women (~30 yr), lending some
support to the idea that aging in both iGH and bGH is in some
way affected by glandular cellular apoptosis (24).
The anterior pituitary glands function and the release of GH
are far from understood as to its release and restoration of GH
isoforms, splice variants, and aggregates back to resting ho-
meostatic concentrations. It appears that the more rapid re-
sponse patterns are related to the 22-kDa iGH isoform but in
J Appl Physiol doi:10.1152/japplphysiol.00599.2016 www.jappl.org
553
much lower concentrations compared with bGH. The systems
complexity, which has been discovered over the past decade,
makes for a fertile area of investigation. An integrated biolog-
ical approach to linking various GH molecular forms to adap-
tive mechanisms and end point outcomes in target tissues such
as muscle and connective tissue remains an important area of
study. Some of the regulatory mechanisms for GH release in
the peripheral circulation may also be related to differential
blood flow control out of the pituitary gland itself, which
remains speculative at best and in need of further investigation.
Figure 2 shows the generalized plasma responses of the ana-
bolic hormones discussed in this review during the recovery
period.
Insulin-like Growth Factor 1 System
IGF-1 is an anabolic and metabolic hormone released by the
liver into the systemic circulation and also produced locally
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(i.e., autocrine and paracrine mechanisms) in tissues and cells
(57, 64). IGF-1 is under exquisite regulation by a family of
binding proteins (IGFBPs 1 6) (13), which are also released
primarily by the liver and can either stimulate or inhibit IGF-1
biological action. The anabolic effects of IGF-1 involve acting
as both a cell cycle initiation and progression factor and center
on satellite cell activation, proliferation, survival, and differ-
entiation (57). The metabolic effects of IGF-1 include stimu-
lating protein synthesis, free fatty acid utilization, and enhanc-
ing insulin sensitivity (13, 21). While liver-derived IGF-1 is
under direct regulation of GH release from the anterior pitu-
itary, local mechanical-stretch mechanisms can also activate
IGF-1 synthesis in local tissues. Many aspects of IGF-1 biol-
ogy (IGF-1 bioavailability, sequestration of IGF-1 across
IGFBPs and biocompartments, IGF-1 receptor activation, etc.)
all contribute to elicit a significant biological impact. The
influence of IGF-1 in mediating some of the beneficial aspects
of exercise particularly with regard to postexercise recovery
and remodeling mechanisms for muscle tissue has been an area
of intense interest (64, 84).
Early cross-sectional reports of an association between cir-
culating IGF-1 and aerobic fitness suggested that IGF-1 could
perhaps be considered a biomarker of health and fitness and an
important mediator of exercise outcomes (17, 64, 65). In a
2011 study that examined circulating IGF-1 and fitness out-
comes in 846 Finnish soldiers, circulating IGF-1 was associ-
ated with higher levels of aerobic fitness and muscular endur-
ance, but not with muscle strength or fat-free mass (65). Even
given the anabolic actions of IGF-1, a direct link between
exercise-induced increases in circulating IGF-1 and subsequent
anabolism for muscle hypertrophy and strength has been dif-
ficult to experimentally determine (31). From a 2010 Point-
Counterpoint on whether IGF-1 was the major regulator of
muscle mass, the ability of IGF-1 to promote muscle hyper-
trophy went unchallenged, but as there is strong evidence that
muscle remodeling is mostly attributed to mechanical strength
and overload, the role of IGF-1 may lie more in being a
regulator or amplifier of muscle remodeling (84). While
West et al. (92) have reported data suggesting similar muscle
anabolic responses to RT under high- or low-GH/IGF environ-
ments, other data indicate a stimulatory effect of IGF-1 on
satellite cell activation and muscle regeneration (14, 15, 31).
However, because of the regulatory complexity governing the
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
precise role IGF-1 has in mediating postexercise recovery (64).
Lending more confusion to understanding the IGF-1 re-
sponse and role in postexercise recovery mechanisms are
conflicting reports in the literature of IGF-1 increases, de-
creases, and no change (26, 42, 61, 64). As a pleiotropic
hormone, it is possible that IGF-1 may be a regulator and/or
amplifier for some overall metabolic influences mediating
exercise-induced responses that are contextual dependent (21,
84). One aspect of IGF-1 physiology that must be considered
with regard to exercise responses is the response of IGFBPs
(38). Of the studies reporting IGF-1 increases postexercise, this
increase is only transient and returns to baseline within 10 30
min. The data for postexercise IGFBP responses are more
consistent (85). Monitoring overnight IGF-1 system concen-
trations following a bout of heavy RE, we have reported that
IGF-1 concentrations remained unchanged but that IGFBP-2
was increased and acid-labile subunit was decreased (63).
These results suggested that the impact of exercise on the
circulating IGF-1 system was not in alterations in the amount
of IGF-1, but rather the manner in which IGF-1 is partitioned
among its family of binding proteins. In a randomized, control
follow-up study in which subjects participated in both aerobic
and RE bouts of differing durations (1 and 2 h), IGFBP-1 was
sensitive to exercise duration, but not exercise mode. IGFBP-1
was increased over the control condition for the 2-h exercise
bouts (94). From a metabolic perspective, this is an important
finding for the IGF-1 system as IGFBP-1 is known to have a
dynamic role in glucose/energy homeostasis. IGFBP-1 is
known to be inversely proportional to insulin and to sequester
free IGF-1. The exercise-induced increase for IGFBP-1 may be
related to modulating IGF-1 bioactivity to match energy flux
demands (13, 38). For example, Bajer et al. (5) have recently
written about IGF-1 as a powerful determinant of exercise-
associated fat mass loss.
In an effort to gain greater insight into the IGF-1 response to
exercise, studies have also been conducted utilizing microdi-
alysis to measure IGF-1 in interstitial fluid (ISF; the fluid
bathing muscle tissue; 66). ISF remains a relatively unexplored
biocompartment that could provide meaningful signature clues
to the mechanotransduction of RE. In subjects who performed
explosive, high-power exercise, total and free IGF-1 and
IGFBP-3 were increased, whereas ISF IGF-1 was unaltered
(ISF IGFBPs were not measured). Of notable interest in this
study, the IGF-1 receptor phosphorylation was not increased,
and IGF mRNA content and Akt phosphorylation were in-
creased. These data reinforce the concept that skeletal muscle
remodeling and adaptation are not simply dependent on an
increase in circulating IGF-1, but rather the interplay between
the IGF system across biocompartments and the mechanotrans-
duction imposed by physical activity. In a recent unpublished
study from our laboratory where ISF IGFBPs were measured in
subjects performing unilateral stretch-shortening cycle exer-
cises until exhaustion, localized and differential IGFBP re-
sponses were observed as IGFBP-3 and -5 were increased only
in the exercised leg. In another application of microdialysis in
understanding IGF-1 physiology and exercise, Hansen et al.
(29) reported that oral contraceptive use resulted in lower
concentrations of circulating and ISF IGF-1 associated with
lower postexercise collagen synthesis. Taken together, the
available evidence points toward the importance of the meth-
odology used to discern the contributory and regulatory roles
of the IGFBP response to postexercise recovery and metabolic
sequelae.

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

 Hormones and Resistance Exercise Kraemer WJ et al.
Local muscle IGF-1 has consistently been shown to be
upregulated with exercise. Using muscle biopsy and immuno-
fluorescence detection of IGF-1, Singh et al. (79) were the first
to report that training-induced increases in muscle IGF-1 were
related to increases in muscle strength. Muscle IGF-1 mRNA
has also been reported to be more influenced by eccentric vs.
concentric muscle contraction (6). Indeed, the mechano-growth
factor (MGF) hypothesis was formulated in addressing the
finding that a splice variant that contains exon 5 increased
above baseline after exercise and that this molecular event was
correlated with mitogenic and myogenic processes (34). How-
ever, Matheny et al. (57) have suggested that it may be
preferable to refer to local IGF-1 as IGF-1Eb (the naturally
occurring splice variant), because MGF is specific to a syn-
thetically manufactured peptide. Further evidence indicates
that the mechanical stimulation of collagen turnover is medi-
ated by local IGF-1 (31, 76).
To summarize, exercise does appear to influence the IGF-1
system, and there are studies to support that these responses are
linked to favorable outcomes related to musculoskeletal health.
Increases in IGFBPs and an upregulation of local IGF-1 are
consistent findings, whereas changes in circulating IGF-1 are
more equivocal. To best understand the role IGF-1 plays in
mediating recovery, it is necessary to consider the spectrum of
IGF-1 regulatory complexity and not rely solely on circulating
IGF-1 itself.
Summary
The elevations in hormones related to anabolic signaling are
just part of a very robust signaling network to support the
homeostatic mechanisms for metabolism and repair. Multiple
targets are involved, of which skeletal muscle is one. The vast
number of pathways and redundancies for coping with exercise
stress is impressive. Increases in the blood concentrations of
these hormones reflect biomarkers that need interpretation
within the context of the muscle tissue activation and the
underlying cellular mechanisms that are at work to carry out
the signaling intentions of the hormonal array. Return to
resting homeostasis is dependent on the rapidity of the target
interactions and need for continued signaling processes.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
W.J.K., N.A.R., and B.C.N. interpreted results of experiments; W.J.K.,
N.A.R., and B.C.N. prepared figures; W.J.K., N.A.R., and B.C.N. drafted
manuscript; W.J.K., N.A.R., and B.C.N. edited and revised manuscript;
W.J.K., N.A.R., and B.C.N. approved final version of manuscript.
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