Highlights
•
PEDs are used professionally & recreationally but can be appropriately detected. •
Evidence does not suggest that GH, IGF-1, or insulin doping enhances performance. •
Community education is needed regarding negative side effects of recreational doping. •
Many PED users engage in polypharmacy, increasing the risk of adverse health events.
Abstract
Hormones with anabolic properties such as growth hormone (GH), insulin-like growth factor-1 (IGF-I), and insulin are commonly abused among professional and recreational athletes to enhance physical ability. Performance enhancing drugs (PEDs) such as these are also commonly used by recreational athletes to improve body aesthetics. The perception of increased muscle mass due to supraphysiologic hormone supplementation, or doping, is widespread among PED users despite a paucity of evidence-based data in humans. Even still, athletes will continue to abuse PEDs in hopes of replicating anecdotal results. It is important to educate the general public and potential treating physicians of the risks of PED use, including the dangers of polypharmacy and substance dependence. It will also be important for the research community to address the common challenges associated with studying PED use such as the ethical considerations of PED administration, the general reticence of the PED-using community to volunteer information, and the constant need to improve or create new detection methods as athletes continually attempt to circumvent current methods. This review highlights the anabolic mechanisms and suggestive data implicating GH, IGF-I, and insulin for use as PEDs, the specific detection methods with cutoff ranges that may be utilized to diagnose abuse of each substance, and their respective side effects.
Keywords
Drug abuse
;
Performance enhancing drugs
;
Muscle
;
Side effects
;
Doping
;
Sports
Introduction
Skeletal muscle is critical for execution of movement, thermogenesis, and nutrient metabolism. Proficiency of these processes is dependent on skeletal muscle mass which is largely regulated by exercise, nutrition, hormones, and to a lesser extent, genetics and ethnicity. As skeletal muscle is a plastic tissue, it responds to progressive overload, such as resistance training, or amino acid ingestion by altering protein synthesis and degradation in favor of tissue growth, or anabolism. Hormones with anabolic properties induce similar responses in skeletal muscle, increasing protein synthesis and/or decreasing protein degradation through a variety of downstream pathways after binding their respective receptors.
Reported enhancements of muscle mass and/or performance from supplementation with exogenous anabolic hormones have encouraged athletes to seek out performance enhancing drugs (PED) for a competitive edge. In an effort to protect elite and professional athletes from the unknown health consequences of PED abuse, the 2004 Anabolic Steroid Control Act expanded the list of controlled substances regulated by the federal government to include naturally occurring precursors of testosterone, growth hormone (GH), and insulin-like growth factor 1 (IGF-I). Although efforts have been made to protect athletes from doping, PED use has also spread to non-professional athletes and to the general population due to ease of access via the web and black market. These individuals have turned to PEDs primarily to improve body aesthetics (Pope et al., 2017) but also to improve energy levels, sex drive, and athletic performance (Creado and Reardon, 2016).
The use of anabolic-androgenic steroids (AAS) such as testosterone and its derivatives has been described extensively (Creado and Reardon, 2016, Pope et al., 2014); however, less attention has been placed on the use of other common PEDs such as GH, IGF-I, and insulin. In 1992, 5% of male high school students admitted to taking GH at some point in their high school sport careers, and about one-third of the participants knew a classmate who had taken GH (Rickert et al., 1992). Middle-aged and elderly people often seek GH with hopes of improving muscle mass and obtaining more youthful physical qualities. PED abuse has also grown in the weightlifting community with 27 of 231 (12%) weightlifters polled reporting past and/or present GH or IGF-I use with over 80% of those polled also exhibiting signs of past or present AAS dependency (Brennan et al., 2011). Insulin is also a commonly used PED by body builders for its purported anabolic properties such as stimulation of glycogen formation, which is important for muscle recovery after exercise, and its accessibility from local pharmacies (Dawson and Harrison, 1997, Evans and Lynch, 2003).
At the molecular level, the balance of anabolic and catabolic (protein degrading) processes is coordinated primarily by the phosphoinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)/Forkhead boxO3a (FOXO3a) pathway among others (Glass, 2005). mTOR is a key mediator contributing to muscle protein synthesis and can be activated by PI3K/Akt (Gulati et al., 2008), which are, in turn, activated by growth factor signaling, such as insulin and IGF-I (Sandri, 2008). Akt phosphorylates, thereby inhibiting, FOXO3a which is a transcription factor that induces the proteosomal pathway by up-regulating the ubiquitin ligases atrogin-1 and muscle RING finger 1 (MuRF-1) (Salih and Brunet, 2008, Stitt et al., 2004). Akt also inhibits glycogen synthase kinase 3 (GSK3), removing the GSK3-induced inhibition of mRNA translation initiation (Leger et al., 2006). Importantly, when the size of a muscle fiber increases, activation of muscle precursor cells, or satellite cells, is required for provision of additional nuclear machinery to support the growing tissue (Hawke and Garry, 2001). Activation of Akt also affects glucose metabolism inducing an increase in glucose and amino acid uptake (Edinger and Thompson, 2002, Kohn et al., 1996). Growth hormone, IGF-I, and insulin are known to influence these pathways, which have provided the basis for their use as PEDs (see Fig. 1).
This review will highlight the pharmacologic basis for and misuse, detection, and side effects of GH, IGF-I, and insulin as PED in sports and the larger recreational community. The impact of polypharmacy will also be addressed as this is an important factor in doping regimens.
Section snippets
Growth hormone
The extent to which GH itself induces significant anabolism is still a matter of debate. Growth hormone's anabolic effects in muscle are mediated in part via IGF-I (Kim et al., 2005), although IGF-I-independent pathways have also been proposed (Daughaday, 1989, Isaksson et al., 1988, Le Roith et al., 2001, Sotiropoulos et al., 2006). IGF-I is made in the liver but also in other tissues including skeletal muscle which express the GH receptor (Jorgensen et al., 2006, Mathews et al., 1986). The
Growth hormone
The emergence of GH as a PED began sometime before 1985 when the first description of its purported effects and recommendations for performance enhancement was published (Duchaine, 1982). Shortly thereafter, Ben Johnson, who won the 100 m gold medal in the Seoul Olympics in 1988, was stripped of his medal after admitting under oath to using GH and anabolic steroids. GH was banned by the International Olympic Committee in 1989 and “off-label” distribution/prescription was declared felonious by
Growth hormone
Unlike anabolic steroids which can be detected by mass spectroscopy from urine samples, GH is measured by immunoassay from blood samples because of low and variable GH excretion levels. However, due to the pulsatile release of GH, detection of elevated GH levels may simply reflect peak circulating levels and not necessarily indicate exogenous GH use. In addition, recombinant human GH is virtually indistinguishable from the endogenous 22-KDa form, including having a very short half-life, with
Growth hormone
A recent workshop comprised of the European Society of Pediatric Endocrinology, Growth Hormone Research Society, and Pediatric Endocrine Society determined that the safety profile of GH administration for indicated purposes (i.e. GH deficiency) was satisfactory (Allen et al., 2016). In contrast, GH administration is not advised for anti-aging in healthy elderly due to increased adverse events (Liu et al., 2007). However, there is little systemic evidence of adverse effects related to GH abuse
Conclusions
Although there is plenty of data on the anabolic potential of GH, IGF-I, and insulin and on their safety and efficacy at physiologic doses, most of this information comes from their therapeutic use in other settings (AGHD, diabetes), or from pathological disorders characterized by hormone hypersecretion (acromegaly, insulinoma). The majority of the data about the abuse of these and other PEDs comes from case reports or uncontrolled studies, underscoring the need for more research in this area.
Conflicts of interests
JMG receives research support from Pfizer (W 1210860). LJA receives research support from the Endocrine Society; Endocrine Scholars Award in Growth Hormone Research supported by Genentec.
Funding
This work was funded by the U.S. Dept of Veterans Affairs (MERIT grants BX002807 and CX000174) and NIH Grant AG040583 to JMG. Dr Anderson is supported by a training grant from the Puget Sound VA RnD office.
Acknowledgements
We thank the University of Washington DERC (P30 DK017047) and NORC (P30 DK035816) for their help. We also thank Dorota Migula for her help in generating the figure.
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