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The authors undertook
a meta-analysis of 26 published (and closely scrutinized) data-sets examining
the relationship between circulating concentrations of IGF-I and IGFBP-3 and
the risk of developing prostatic, breast, colon, and lung cancer in adult men
and women employing extremely strict, unified, and sensitive analytical
methods. After stratification of the analyte levels, they compared the 75th
percentile of circulating protein concentration with the 25th
percentile and then calculated odds ratios for the development of cancer. There
were significant associations between the concentration of IGF-I and
development of premenopausal breast, prostatic, and colon cancer (odds ratios:
1.93, 1.83, and 1.58, respectively). There was no association between IGF-I
values and risk of breast cancer in postmenopausal women or of lung cancer. The
IGFBP-3 level was associated with an increased risk of development of breast
cancer in premenopausal women (odds ratio 1.96) and possibly with a protective
effect on development of lung cancer. The investigators concluded that because
of the proliferative and anti-apoptotic effects of various IGFs, higher
circulating concentrations of IGF-I are a risk factor for development of 3
non-smoking related common malignancies.
Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363:1346-1353.
First Editor’s Comment: The association of
hyper-somatotropism with increased risk for development of cancer of the colon
is well known.1 The present report concluded that higher IGF-I
concentrations contributed to the development of several malignancies. The
mechanism(s) by which IGF-I enhanced or facilitated neoplasia and the roles
that IGFBPs and IGFBP proteases (such as prostate specific antigen) played in
this process are not known with certainty.2 The precise point at
which a malignancy began and the corresponding IGF-I value is unknown. However,
the association between IGF-I concentrations and malignancy should give one
pause when recommending the use of growth hormone (GH) in short subjects
without GH deficiency, particularly in the absence of data indicating that an
increment in adult height of 2 or more inches results in greater academic,
social, and economic well-being.
Allen W. Root, M.D
Second Editor’s Comment: The major lesson from
the IGF/cancer association is to beware of over generalizations; this is a
story of complicated nuances. Over 200,000 patient-years’ experience globally
with recombinant human growth hormone (rhGH) therapy revealed a very strong
safety profile. This safety profile may not hold as our use moves from purely
physiologic replacement to increasingly pharmacologic use, in terms of both
higher doses and newer indications. For example, increased mortality ensued
when rhGH was administered to critically ill adults in an attempt to foster
anabolism.3 Conversely, we cannot jump to the conclusion that IGF-1
(and GH) are necessarily harmful. While high IGF-1 levels have been associated
with higher cancer risk, low IGF-1 levels have been associated with increased
risk for age-related memory loss, Alzheimer’s dementia and diabetes-associated
dementia.
The underlying science is also filled with
nuances that likely contribute to the contradictory results found in the
literature. The relative contributions of endocrine (circulating) versus
autocrine or paracrine GH/IGF axis components to cancer progression remain
unclear and technical issues, such as IGFBP interference with some IGF assays4
and interassay variations,5 can cloud the results. Due to its
dynamic nature, measuring components of the IGF system may yield different
results, ie a shift in the amount of free versus total IGF, the IGFBP profile,
or the amount of intact versus proteolyzed IGFBP.
More research is needed, as in long-term
surveillance of the rhGH recipients into late adulthood when the natural
incidence of cancer increases. As a safety marker, IGF-1 levels should be
closely monitored in all rhGH recipients to avoid supraphysiologic
concentrations. Clinical nuances may also be explored regarding potential risk
modulation by altering rhGH dose or duration of treatment.4 Ultimately,
treatment should be individualized and tailored to the risk/benefit analysis
for each patient. That includes appreciating the true benefit (or not) of
height augmentation.
Adda Grimberg, MD
References - (linked to  )
- Wolk A. The growth hormone and insulin-like growth factor I axis, and cancer. Lancet 2004;363:1336-1337.
- Grimberg A. Mechanisms by which IGF-I may promote cancer. Cancer Biol Ther. 2003 Nov-Dec;2(6):630-5
- Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999 Sep 9;341(11):785-92
- Grimberg A, Cohen P. Growth hormone and prostate cancer: guilty by association? J Endocrinol Invest. 1999;22(5 Suppl):64-73
- Milani D, Carmichael JD, Welkowitz J, Ferris S, Reitz RE, Danoff A, Kleinberg DL. Variability and reliability of single serum IGF-I measurements: impact on determining predictability of risk ratios in disease development. J Clin Endocrinol Metab. 2004 May;89(5):2271-4.
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Current GGH - Vol. 24 No. 1
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