Growth hormone, IGF-I and insulin and their abuse in sport

Abstract

There is widespread anecdotal evidence that growth hormone (GH) is used by athletes for its anabolic and lipolytic properties. Although there is little evidence that GH improves performance in young healthy adults, randomized controlled studies carried out so far are inadequately designed to demonstrate this, not least because GH is often abused in combination with anabolic steroids and insulin. Some of the anabolic actions of GH are mediated through the generation of insulin-like growth factor-I (IGF-I), and it is believed that this is also being abused. Athletes are exposing themselves to potential harm by self-administering large doses of GH, IGF-I and insulin. The effects of excess GH are exemplified by acromegaly. IGF-I may mediate and cause some of these changes, but in addition, IGF-I may lead to profound hypoglycaemia, as indeed can insulin. Although GH is on the World Anti-doping Agency list of banned substances, the detection of abuse with GH is challenging. Two approaches have been developed to detect GH abuse. The first is based on an assessment of the effect of exogenous recombinant human GH on pituitary GH isoforms and the second is based on the measurement of markers of GH action. As a result, GH abuse can be detected with reasonable sensitivity and specificity. Testing for IGF-I and insulin is in its infancy, but the measurement of markers of GH action may also detect IGF-I usage, while urine mass spectroscopy has begun to identify the use of insulin analogues.

Figure 1

The growth hormone (GH)–insulin-like growth factor (IGF)-I axis. GH is secreted from the pituitary gland under the control of the hypothalamic hormones, somatostatin, Ghrelin and GH-releasing hormone (GHRH). GH circulates bound to its binding protein and acts through specific cell-surface receptors. The anabolic actions of GH are partially mediated by IGF-I. IGF-I acts through the IGF-I receptor in an autocrine, paracrine and classical endocrine mechanisms. Circulating IGF-I is almost entirely bound to a family of high-affinity binding proteins (IGFBPs) that coordinate and regulate the biological functions of the IGFs. IGF-I inhibits GHRH and GH secretion in a classical negative-feedback mechanism.

Figure 2

The synergistic action between insulin, IGF-I and GH in regulating protein synthesis. Without insulin, GH loses much (if not all) of its anabolic action. GH and IGF-I stimulate protein synthesis directly, whereas insulin is anabolic through inhibition of protein breakdown. The anabolic action of both GH and IGF-I appears to be mediated through induction of amino-acid transporters in the cell membrane. It is not yet clear how much of the action of IGF-I is through locally generated IGF-I (‘autocrine' and ‘paracrine') or through circulating IGF-I that is largely derived from the liver.

Figure 3

Principle of the isoform method. rhGH contains 22 kDa and this is specifically recognized by assay 1. Pituitary GH contains multiple isoforms and these are recognized by assay 2. When rhGH is administered, endogenous production of pituitary GH decreases, and therefore the ratio between assay 1 and assay 2 increases after rhGH administration.

Figure 4

Ratio between 22 kDa-hGH assay and total hGH assay in serum samples obtained from 125 controls and 30 individuals treated with rhGH. Mean values are 1.43±0.21 for treated individuals and 0.50±0.12 for controls (P<0.0001). Adapted from Wu et al. (1999). Figure reproduced with the permission of Christian Strasburger.

Figure 5

Change in IGF-I (a) and P-III-P (b) following the administration of GH or placebo for 28 days to 50 healthy male volunteers.

Figure 6

Change in GH-2000 score in men (a) and women (b) following 28 days of GH administration. Dotplot of the standardized scores for each visit day of the studies by group and data set. The mean of a normal population is 0 and the standard deviation is 1. Using a pre-defined sensitivity of 1 in 10 000, samples with a score of >3.7 are identified correctly as receiving GH (labelled as ‘doped'). Note none of the baseline or placebo values are above 3.7.