CLINICAL PERSPECTIVE: Acromegaly and Cancer: A Problem

Paul J. Jenkins and Michael Besser

Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE

Address all correspondence and requests for reprints to: Dr. Paul Jenkins, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE. E-mail: p.j.jenkins{at}mds.qmw.ac.uk

Since the original description by Pierre Marie over a century ago, acromegaly has been known to be associated with an increased morbidity and mortality. Early epidemiological reviews suggested that this was due largely to cardiovascular, cerebrovascular, respiratory, and metabolic diseases. However, more recently, studies such as that by Ezzat and Melmed (1) have suggested that these patients currently are also at increased risk for cancer, particularly colorectal; some suggestions have been made that there is a risk of breast, prostate, and possibly hematological malignancies (2, 3) (Table 1Go). Some of the difficulty in determining the true incidence of cancer in this condition results from the relative rarity of acromegaly itself, which makes it difficult for individual centers to gather sufficient numbers of patients for statistical analysis. A further important factor is that it is only with improved treatment of the other complications that patients with acromegaly are now surviving long enough to reach the age of increased cancer risk. In the early series by Wright et al. (64) and Alexander et al. (65), approximately 50% of patients had died before the age of 60 yr; it is clearly inappropriate to use early reviews to draw conclusions relating to cancer risk in patients exposed to current improved practice because patients are now living much longer, and the development of malignancy in these patients appears to be age related. The establishment of the true prevalence of cancer in acromegaly requires current data and will become clearer with multicenter analysis, such as that of acromegaly registers being collated in the United Kingdom and U.S.


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Table 1. Retrospective epidemiological reviews of occurrence of malignant disease in patients with acromegaly

 
Colorectal cancer and tubulo-villous adenomas

Colorectal cancer. Of all cancers, evidence is strongest for an increased risk in acromegaly of colorectal cancer (Table 2Go), and this is now regarded by many researchers and consensus working groups as being a major complication of this disease (1, 2, 3, 4, 5, 6, 7). The cancer surveillance program at St. Bartholomew’s Hospital was initiated after the publication of one of the earliest reports detailing an increased prevalence of colonic neoplasia by Ezzat and Melmed (8). In that study of 26 patients, 3 had colorectal cancer, and 8 had tubulo-villous adenomas. Of the 155 asymptomatic patients with acromegaly aged over 50 yr investigated at St. Bartholomew’s Hospital with full-length colonoscopic examination, 10 (6.5%) have been found to have adenocarcinoma. Although, in common with several other series, this study did not include asymptomatic matched controls, the relative risk can be assessed by comparison with published series of screened asymptomatic nonacromegalic patients (Table 3Go). These analyses give a relative risk of between 6.8- and 18.3-fold. That this increased risk is not restricted to our center is supported by grouping all of the prospective series of colonoscopic screening of patients with acromegaly: a total of 25 cancers have been detected in 681 patients (3.7%), compared with a rate of 0.5% among control subjects in those series with concurrent control groups (relative risk, 13.4; P < 0.00001). Even a recent study that reported no increased rate of colorectal neoplasia recorded cancers in 2.6% of asymptomatic patients with acromegaly (9). An increasing amount of data suggests that the prevalence of colorectal cancer is significantly increased in acromegaly, and in common with other researchers, we regard these patients as being at high risk of developing this malignancy (1, 3, 4, 6, 10).


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Table 2. Retrospective and prospective studies of screening for colorectal neoplasia in patients with acromegaly

 

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Table 3. Relative risk of the prevalence of colorectal cancer (CRC) in patients with acromegaly determined by comparison of prevalence rates from St. Bartholomew’s Hospital and other published series to large scale screening studies of asymptomatic nonacromegalic subjects

 
Tubulo-villous adenomas

In nonacromegalic patients, the majority of colorectal cancers arise from tubular adenomas, a process that is thought to take approximately 10 yr. Particularly bad prognostic signs are a severe degree of cellular dysplasia within the adenoma and a size greater than 10 mm. In common with colorectal cancer, numerous studies have demonstrated an increased prevalence of these premalignant polyps in acromegaly with rates of between 9–40%. Several reasons account for these variations. As in the general population, age is a major determinant of their prevalence in acromegaly (9, 11, 12, 13); in one large series adenomas occurred in only 8% of patients aged less than 40 yr, 12% of those aged 40–49 yr, 26% of those aged 50–59 yr, 30% of those aged 60–69 yr, and 33% of those over 70 yr of age (13). Series that have recorded a lower overall prevalence rate in acromegaly have often studied younger patients than those that report an increased age-related prevalence (14). Another important variable is the need to visualize the entire colon. In some series the cecum was reached in only about 70% of patients (14, 15); improved visualization to the cecum is associated with a higher prevalence rate, as the lesions occur at the right side of the colon more often than is usually found in other patient groups (13, 16, 17).

In common with the data on cancer, the absence of simultaneous control groups in some series of patients with acromegaly has been used to play down the significance of the findings. However, comparison of these data with those from series with matched control groups confirm the increased prevalence in acromegaly (Table 2Go). Grouping of these various studies gives an overall prevalence rate in acromegaly of 21% compared with 9% for controls (relative risk, 2.36, 95% confidence interval, 1.8–3.1; P < 0.0001). This mean prevalence among controls accords with the 9–10% reported in a number of published series of colonoscopic screenings of asymptomatic nonacromegalic patients. However, a recent large scale study of nonacromegalic subjects found a higher rate of 37% (18). There are several reasons for the discrepancy relating to the latter study: 1) the patients were all males, and males are known to have an increased incidence of colorectal neoplasia; and 2) there was a marked selection bias in that of the available 17,732 patients, only 3,196 were selected for screening, 50% of whom had been referred by their medical practitioner for unspecified reasons. There was also a positive selection toward those with a family history of colonic cancer. That this study overestimated the prevalence of adenoma detected by colonoscopy in the general population is indicated by a simultaneously published study of colonoscopic screening of almost 2,000 asymptomatic subjects among whom the prevalence rate was again 9.6% (19).

The majority of studies report an increased prevalence of colonic adenomas in acromegaly, but a recent study published in this journal failed to do so (9). Indeed, the observed prevalence in that report is the lowest of all series of patients with acromegaly. However, many of the patients were studied at an earlier age (mean, 54.8 yr; range, 25–82 yr). If the prevalence of tubulo-villous adenomas is assessed only in those patients reported in this study over the age of 50 yr, the prevalence is 20%, not different from that in other series of patients with acromegaly and clearly greater than the generally accepted control prevalence of around 9%. Despite the claim to the contrary, these observations confirm the increased risk of colonic neoplasms in the older patients with acromegaly. Furthermore, the autopsy-based second control group is not comparable to the group of acromegalic patients; not only are the subjects elderly, but the resected bowel obtained at autopsy is washed several times and repeatedly examined in optimal lighting, often under a microscope, and lesions as small as 1 mm are recorded. This is far different from the in vivo situation in acromegalic patients, in whom the colon is larger, more cavernous, and with frequently difficult visualization (10, 20). Indeed, such limitations are likely to underestimate the true prevalence rate in acromegaly.

Characteristics of colorectal neoplasia in acromegaly. In addition to its increased overall incidence, there is evidence that colorectal neoplasia in acromegaly has different characteristics compared with those in the general population. The lesions are more likely to be right sided, with up to 68% of adenomas being situated in the ascending or transverse colon (9, 12, 15, 17, 21); 3 of the 10 carcinomas in the Bart’s series were at the cecum. The adenomas also tend to be larger, with 1 series reporting a mean diameter of 18 mm compared with 9 mm in controls (P < 0.001) (9, 15, 17). Several groups have also reported that the adenomas tend to be more dysplastic, with up to 64% being classified as moderately to severely dysplastic (9, 17). Finally, the adenomas are more often multiple in patients with acromegaly (9, 11, 12, 21, 22, 23). These altered characteristics suggest that not only do adenomas occur more frequently in acromegaly, but they behave more aggressively, with an increased tendency for malignant progression.

Influence of serum GH and insulin-like growth factor I (IGF-I) on colorectal neoplasia. In nonacromegalic subjects, the colonic epithelium is arranged in crypts, with actively dividing cells located at the base that then move up the crypt toward the lumenal surface to undergo apoptosis. Increased proliferation is the preliminary step in adenoma formation, leading to an increased chance of an oncogenic mutation in the adenomatosis polyposis coli gene, the initial mutation in colorectal tumorigenesis. IGF-I is a known mitogen in many tissues and stimulates the growth of colorectal cancer cells in vitro (24, 25). We and others have shown increased proliferation of the colonic epithelium in acromegaly, proportional to serum IGF-I levels (26, 27). However, some studies of patients with acromegaly have shown no association between serum IGF-I levels and the presence of neoplasia (11), whereas others have shown a significant association (9, 15, 17), including a large retrospective review that demonstrated a positive association between mortality from colorectal cancer in acromegaly and disease activity (28). There is uncertainty as to how long adenomas/carcinomas have actually been present when detected at the time of colonoscopy; therefore, the relationship between IGF-I levels and development of the adenoma is uncertain. A clearer prospective study has been provided in patients who have had removal of adenomas at an initial colonoscopy followed by review with a second colonoscopic evaluation at intervals after the original screening examination. We recently completed this for 66 of our original cohort of patients at a mean interval of 33 months (range, 3–76 months). Newly developed adenomas were detected in 14% of patients, and their occurrence was significantly related to both serum GH (P < 0.05) and IGF-I levels (P < 0.005). This would be consistent with the idea that a raised IGF-I level is relevant at the time that the adenoma develops rather than when it is subsequently discovered and that elevated circulating GH/IGF-I is implicated in colorectal tumorigenesis in acromegaly (29). This is in keeping with recent epidemiological studies in nonacromegalic subjects that have demonstrated a positive association between the development of colorectal cancer and serum IGF-I levels in the upper, rather than the lower, part of the normal range (30, 31).

In addition to its proliferative actions, IGF-I exerts marked antiapoptotic effects in a variety of tissues (32, 33). IGF-I prevents butyrate-induced apoptosis in HT-29 and Caco-2 colorectal cancer cells, and the increased colonic epithelial proliferation in acromegaly is accompanied by significantly reduced apoptosis and a disordered pattern of the Bcl-2 family of apoptotic proteins (34). The precise mechanisms by which IGF-I might cause these effects remain uncertain. One possibility involves the inappropriate induction of c-myc transcription. Both GH and IGF-I have been shown to activate c-myc transcription in vivo, and this gene is up-regulated in 70–90% of colorectal cancers at an early stage (35, 36). c-myc is regarded as playing a central role in sporadic colorectal tumorigenesis regulating the transcription of numerous genes that are intimately involved in proliferation, apoptosis, angiogenesis, and metastases.

In addition to GH and IGF-I, alterations in the intracolonic environment might also play a role in the development of neoplasia in acromegaly. One such factor relates to bile acids and, in particular, the unconjugated secondary bile acid, deoxycholic acid (DCA). This is formed in the cecum by bacterial deconjugation and dehydroxylation of the primary bile acid, cholic acid. Serum levels of unconjugated DCA have been shown to reflect intraluminal concentrations and are much higher in nonacromegalic patients with colorectal neoplasia than in age-matched normal subjects (37, 38). Levels of serum unconjugated DCA are, on the average, 3 times higher in acromegaly than in nonacromegalic control subjects; patients with acromegaly and colonic neoplasia have even higher levels than those without neoplasms (39). The mechanisms for this increase in DCA concentrations relate both to a prolonged colonic transit and an increased intraluminal bacterial activity (40).

Guidelines for colonoscopic screening. In the nonacromegalic population, it has been demonstrated that colonoscopic screening and removal of adenomas reduce the incidence of subsequent carcinoma, thus suggesting that colorectal cancer is to some extent a preventable disease (41). As patients with acromegaly are at increased risk of colonic cancer, they should be offered regular colonoscopic screening (5, 6, 42). The question arises as to when this should begin and how often it should be repeated. In nonacromegalic subjects, a single sigmoidoscopy at the age of 55 yr has been proposed by some authorities as being sufficient (43). We believe that this is inadequate and that patients with acromegaly should be regarded as a high risk group, similar to patients with a strong family history of colorectal cancer (10). In our series of repeat colonoscopic evaluations, all but two of the patients with new adenoma had had an adenoma at the original screening (29). Our youngest patient with a carcinoma was aged 58 yr, and our youngest patient with an adenoma was 40 yr. We suggest that it would be prudent to offer routine surveillance similar to other at risk groups. A conservative approach would be initial screening at the age of 40 yr with subsequent reevaluation intervals dependent on the colonoscopic findings and disease activity. When an adenoma is found, or if the serum IGF-I level is still elevated, repeat screening should occur after 3 yr. A normal full-length screening colonoscopy or the presence of a hyperplastic polyp should warrant screening at 5-yr intervals. Naturally, these preliminary guidelines will need to be amended in the light of further data.

There are several practical issues that determine the success of colonoscopy in patients with acromegaly. Their increased colonic length and circumference, as well as prolonged colonic transit time mean that standard bowel preparation is usually inadequate (20, 40). In the authors’ experience, 6 L Kleen-Prep (Norgine, Harefield, UK) instead of the usual 3 L are generally required, with 2 L given at 6, 4, and 2 h before the procedure, with a liquid only diet for the preceding 24 h. In view of the technical difficulties of the examination, an experienced colonoscopist should perform the procedure, as in inexperienced hands the cecum is reached in only approximately 75% of cases (10). This is particularly important given the propensity toward right-sided lesions.

In conclusion, a number of studies have confirmed that acromegaly is associated with an increased prevalence of colorectal neoplasia, and as such, these patients should be regarded as being at high risk for developing this complication. Regular colonoscopic screening and polypectomy will reduce the incidence of subsequent carcinoma among these patients. The demonstration of a clear relation to serum GH and IGF-I levels is further indication for more aggressive management of the underlying acromegaly.

Other malignancies

Breast carcinoma. In addition to colorectal cancer, a number of reviews have indicated that patients with acromegaly may be also at increased risk of developing breast carcinoma (7, 44, 45, 46, 47) with one study suggesting a 4-fold increase in risk (44). Determining the true incidence, however, is made more difficult by the restriction to female patients, which halves the number of patients at any single center. This has to some extent been overcome by a large multicenter retrospective review of more than 1200 patients that demonstrated an almost 2-fold increase in mortality from breast carcinoma, although other clinical studies in acromegalic patients are limited (28). There is also circumstantial evidence to suggest that patients with acromegaly might be at increased risk of developing breast cancer. Two early epidemiological studies have related the GH/IGF-I axis to breast carcinoma in the general population, in that patients with breast carcinoma had significantly higher serum GH or IGF-I levels compared with subjects without carcinoma (48, 49). A subsequent prospective review showed that a serum IGF-I level in the upper part of the normal range was associated with a significant increased risk of developing this cancer (50). Further prospective studies are required to establish whether there is truly an increased risk.

Some of the earliest work relating the GH/IGF-I axis to breast carcinoma was provided in the 1950s by Moon et al., who demonstrated the occurrence of mammary neoplastic change in female rats injected long term with GH (51). It has also long been known that hypophysectomy is associated with disease remission in patients with metastatic breast carcinoma, even in previously ovariectomized women (52). In vitro, IGF-I causes marked proliferation of human breast cancer cell lines (53, 54, 55), results complemented by in vivo experiments using infusions of GH and/or IGF-I to monkeys (56). Significant increases in the size of the mammary glands and proliferation of the epithelium were observed in response to both GH (3- to 4-fold) and the combination of GH and IGF-I (4- to 5-fold). These changes correlated with serum GH/IGF-I levels, which were comparable to those seen in acromegaly. Further evidence is suggested by transgenic human GH mice, which have elevated plasma GH levels and an increased incidence of mammary tumors (57). Conversely, other models have used the lit mouse, in which there is a functional defect of the GHRH receptor and decreased serum GH levels (58). Transplantation of human breast cancer cells into these mice results in approximately 50% decreased cancer growth compared with controls.

The number of studies showing an increase in breast cancer incidence in females with acromegaly is limited, but there is some evidence relating the GH/IGF-I axis and breast cancer in the nonacromegalic population. Further studies are required.

Prostate cancer. Evidence linking prostatic carcinoma and acromegaly is circumstantial. This may be because the disease is limited to elderly men, and it has not been until recently that these patients with acromegaly have survived long enough to become available for epidemiological studies. Significant prostatic enlargement has been demonstrated in young (<40-yr-old) patients with acromegaly compared with age-matched controls (mean volume, 28 vs. 18 mL, respectively; P < 0.001), with a higher than expected prevalence of micro- and macrocalcification (59). This hyperplasia resolved with lowering of GH levels. In a recent cross-sectional survey of acromegalic men aged over 50 yr, an elevated serum prostate-specific antigen was detected in 17%, which represented 46% of those aged over 65 yr, with one patient having a metastatic prostate cancer (60). In a retrospective review of nonacromegalic men, those with histologically proven prostate carcinoma were found to have serum IGF-I levels higher than control levels, although still within the normal range (61, 62). The relative risk was estimated at 1.9 for each 60 mg/mL increment in serum IGF-I, but increased almost 7-fold in the presence of a higher serum testosterone level. These findings were supported by a recent prospective study in which a serum IGF-I level in the upper quintile of the normal range was associated with a significantly increased risk of developing prostate cancer, which was increased to almost 18-fold for men aged over 60 yr of age (63).

Thus, although direct evidence is limited, these data suggest that the incidence of prostatic carcinoma in male patients with acromegaly may be increased, although well controlled studies have not been published. Given this, increased surveillance of these patients is warranted, with the highest theoretical risk being in elderly men with persistent elevated serum IGF-I who are receiving testosterone replacement.

Conclusions

In summary, the evidence of an increased risk of colorectal cancer in acromegaly is now strong. Such patients should be considered as a high risk group for the development of this neoplasia, which is related to disease activity. These patients should be offered regular colonoscopic screening, although the optimal frequency of this has yet to be finally determined. Determination of the pathogenesis of colorectal cancer in these patients will offer significant information about the role of the GH/IGF-I axis in colorectal tumorigenesis in the general population. There is circumstantial evidence suggesting that breast and prostate malignancies may also be increased in acromegaly, but the true incidence will await the outcome of large scale epidemiological studies. As cancer is generally a disease of increasing age; the current trend toward improved survival of patients with acromegaly may reveal an increased prevalence of cancer in the future.

Received January 4, 2001.

Revised February 27, 2001.

Accepted March 2, 2001.

References

  1. Ezzat S, Melmed S. 1991 Clinical review 18: are patients with acromegaly at increased risk for neoplasia?. J Clin Endocrinol Metab. 72:245–249.[Medline]
  2. Melmed S, Ho K, Klibanski A, Reichlin S, Thorner M. 1995 Clinical review 75: recent advances in pathogenesis, diagnosis, and management of acromegaly. J Clin Endocrinol Metab. 80:3395–3402.[Medline]
  3. Melmed S, Jackson I, Kleinberg D, Klibanski A. 1998 Current treatment guidelines for acromegaly. J Clin Endocrinol Metab. 83:2646–2652.[Abstract/Free Full Text]
  4. Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, et al. 2000 Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab. 85:526–529.[Abstract/Free Full Text]
  5. Turner HE, Wass JA. 2000 Modern approaches to treating acromegaly. Q J Med. 93:1–6.[Free Full Text]
  6. Klein I. 1984 Acromegaly and cancer. Ann Intern Med. 101:706–707.[Medline]
  7. Popovic V, Damjanovic S, Micic D, et al. 1998 Increased incidence of neoplasia in patients with pituitary adenomas. The Pituitary Study Group. Clin Endocrinol (Oxf). 49:441–445.[CrossRef][Medline]
  8. Ezzat S, Strom C, Melmed S. 1991 Colon polyps in acromegaly. Ann Intern Med. 114:754–755.[Medline]
  9. Renehan AG, Bhaskar P, Painter JE, O’Dwyer ST, Haboubi N, Ball SG, et al. 2000 The prevalence and characteristics of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab. 85:3417–3424.[Abstract/Free Full Text]
  10. Jenkins PJ, Besser GM, Fairclough PD. 1999 Colorectal neoplasia in acromegaly. Gut. 44:585–587.[Free Full Text]
  11. Terzolo M, Tappero G, Borretta G, et al. 1994 High prevalence of colonic polyps in patients with acromegaly. Influence of sex and age Arch Intern Med. 154:1272–1276.[Abstract]
  12. Delhougne B, Deneux C, Abs R, et al. 1995 The prevalence of colonic polyps in acromegaly: a colonoscopic and pathological study in 103 patients. J Clin Endocrinol Metab. 80:3223–3226.[Abstract]
  13. Jenkins PJ, Fairclough PD, Richards T, et al. 1997 Acromegaly, colonic polyps and carcinoma. Clin Endocrinol (Oxf). 47:17–22.[Medline]
  14. Ladas SD, Thalassinos NC, Ioannides G, Raptis SA. 1994 Does acromegaly really predispose to an increased prevalence of gastrointestinal tumours? Clin Endocrinol (Oxf). 41:597–601.[Medline]
  15. Vasen HF, van Erpecum KJ, Roelfsema F, et al. 1994 Increased prevalence of colonic adenomas in patients with acromegaly. Eur J Endocrinol. 131:235–237.[Medline]
  16. Hussaini SH, Murphy GM, Kennedy C, Besser GM, Wass JA, Dowling RH. 1994 The role of bile composition and physical chemistry in the pathogenesis of octreotide-associated gallbladder stones. Gastroenterology. 107:1503–1513.[Medline]
  17. Colao A, Balzano A, Ferone D, et al. 1997 Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly. Clin Endocrinol. 47:23–28.[Medline]
  18. Lieberman DA, Weiss DG, Bond JH, Ahnen DJ, Garewal H, Chejfec G. 2000 Use of colonoscopy to screen asymptomatic adults for colorectal cancer. N Engl J Med. 343:162–168.[Abstract/Free Full Text]
  19. Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF. 2000 Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal findings. N Engl J Med. 343:169–174.[Abstract/Free Full Text]
  20. Jenkins PJ, Mills TD, Veysey MJ, Reynolds CR, Dowling RH, Besser GM. 1997 Acromegaly is associated with colonomegaly which correlates with tissue exposure to growth hormone and may be implicated in their increased risk of colorectal neoplasia. J Endocrinol. 155(Suppl 2):OC22.
  21. Tzoiti M, Akriviadis A, Papadopoulou E, et al. Colon polyps prevalence in acromegalic patients. Proc of the 82nd Annual Meet of The Endocrine Soc. 2000; 2028.
  22. Klein I, Parveen G, Gavaler JS, Vanthiel DH. 1982 Colonic polyps in patients with acromegaly. Ann Intern Med. 97:27–30.[Medline]
  23. Archambeaud-Mouveroux F, Geffray I, Teissier MP, Galinat S, Sautereau D, Pillegand B. Prevalence of colorectal carcinoma and polyps in acromegaly. Proc of the 80th Annual Meet of The Endocrine Society, 1998; P2–504.
  24. Durrant LG, Watson SA, Hall A, Morris DL. 1991 Co-stimulation of gastrointestinal tumour cell growth by gastrin, transforming growth factor {alpha} and insulin like growth factor-I. Br J Cancer. 63:67–70.[Medline]
  25. Lahm H, Suardet L, Laurent PL, et al. 1992 Growth regulation and co-stimulation of human colorectal cancer cell lines by insulin-like growth factor I, II and transforming growth factor {alpha}. Br J Cancer. 65:341–346.[Medline]
  26. Cats A, Dullaart RP, Kleibeuker JH, Kuipers F, Sluiter WJ. 1996 Hardonk et al. Increased epithelial cell proliferation in the colon of patients with acromegaly. Cancer Res. 56:523–526.[Abstract]
  27. Stellini M, Jenkins PJ, Fairclough P, et al. 1999 The pathogenesis of colorectal neoplasia in acromegaly. 17th United European Gastroenterology Week; p 645.
  28. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab. 83:2730–2734.[Abstract/Free Full Text]
  29. Jenkins PJ, Frajese V, Jones A-M, et al. 2000 IGF-I and the development of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab. 85:3218–3221.[Abstract/Free Full Text]
  30. Manousos O, Souglakos J, Bosetti C, et al. 1999 IGF-I and IGF-II in relation to colorectal cancer. Int J Cancer. 83:15–17.[CrossRef][Medline]
  31. Ma J, Pollak M, Giovannucci E, et al. 1999 Prospective study of colorectal cancer risk in men and plasma levels of insulin like growth factor (IGF)-1 and IGF-binding protein-3. J Natl Cancer Inst. 91:620–625.[Abstract/Free Full Text]
  32. Remacle-Bonnet MM, Garrouste FL, Heller S, Andre F, Marvaldi JL, Pommier GJ. 2000 Insulin-like growth factor-I protects colon cancer cells from death factor-induced apoptosis by potentiating tumor necrosis factor {alpha}-induced mitogen-activated protein kinase and nuclear factor {kappa}B signaling pathways. Cancer Res. 60:2007–2017.[Abstract/Free Full Text]
  33. Prisco M, Romano G, Peruzzi F, Valentinis B, Baserga R. 1999 Insulin and IGF-I receptors signaling in protection from apoptosis. Horm Metab Res 31:80–89.
  34. Dash S, Jones A-M, Jordan S, Lowe DG, Fairclough PD, Jenkins PJ. 1999 Expression of the apoptotic proteins BCL-2 and BAX in normal and neoplastic colonic epithelium from patients with and without acromegaly. J Endocrinol. 163(Suppl):21.
  35. Murphy LJ, Bell GI, Friesen HG. 1987 Growth hormone stimulates sequential induction of c-myc and insulin-like growth factor I expression in vivo. Endocrinology. 120:1806–1812.[Abstract]
  36. Sumantran VN, Feldman EL. 1993 Insulin-like growth factor I regulates c-myc and GAP-43 messenger ribonucleic acid expression in SH-SY5Y human neuroblastoma cells. Endocrinology. 132:2017–2023.[Abstract]
  37. Bayerdorffer E, Mannes GA, Richter WO, et al. 1993 Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology. 104:145–151.[Medline]
  38. Bayerdorffer E, Mannes GA, Ochsenkuhn T, Dirschedl P, Wiebecke B, Paumgartner G. 1995 Unconjugated secondary bile acids in the serum of patients with colorectal adenomas. Gut. 36:268–273.[Abstract]
  39. Jenkins PJ, Veysey MJ, Thomas LA, et al. 1997 Increased serum deoxycholic acid levels in acromegalic patients with colorectal neoplasia. J Endocrinol. 152(Suppl):74.
  40. Hussaini SH, Pereira SP, Veysey MJ, et al. 1996 Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide induced gall bladder stones. Gut. 38:775–783.[Abstract]
  41. Atkin WS, Morson BC, Cuzick J. 1992 Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med. 326:658–662.[Abstract]
  42. Melmed S. 1998 Tight control of growth hormone: an attainable outcome for acromegaly treatment. J Clin Endocrinol Metab. 83:3409–3410.[Free Full Text]
  43. Selby JV, Friedman GD, Quesenberry Jr CP, Weiss NS. 1992 A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med. 326:653–657.[Abstract]
  44. Nabarro JD. 1987 Acromegaly. Clin Endocrinol (Oxf). 26:481–512.[Medline]
  45. Bengtsson BA. 1993 Acromegaly and neoplasia. J Pediatr Endocrinol. 6:73–78.[Medline]
  46. Barzilay J, Heatley GJ, Cushing GW. 1991 Benign and malignant tumors in patients with acromegaly. Arch Intern Med. 151:1629–1632.[Abstract]
  47. Ritchie CM, Atkinson AB, Kennedy AL, et al. 1990 Ascertainment and natural history of treated acromegaly in Northern Ireland. Ulster Med J. 59:55–62.[Medline]
  48. Emerman JT, Leahy M, Gout PW, Bruchovsky N. 1985 Elevated growth hormone levels in sera from breast cancer patients. Horm Metab Res. 17:421–424.[Medline]
  49. Peyrat JP, Bonneterre J, Hecquet B, et al. 1993 Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer. Eur J Cancer. 29A:492–497.
  50. Hankinson SE, Willett WC, Colditz GA, et al. 1998 Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 351:1393–1396.[CrossRef][Medline]
  51. Moon HD, Simpson ME, Li CH, Evans HM. 1950 Neoplasms in rats treated with pituitary growth hormone. I. Pulmonary and lymphatic tissues. Cancer Res. 10:297–308.
  52. Ray BS, Pearson OH. 1962 Hypophysectomy in treatment of disseminated breast cancer. Surg Clin North Am. 12:419–433.
  53. Pollak MN. 1998 Endocrine effects of IGF-I on normal and transformed breast epithelial cells: potential relevance to strategies for breast cancer treatment and prevention. Breast Cancer Res Treat. 47:209–217.[CrossRef][Medline]
  54. Xie SP, Pirianov G, Colston KW. 1999 Vitamin D analogues suppress IGF-I signalling and promote apoptosis in breast cancer cells. Eur J Cancer. 35:1717–1723.[CrossRef][Medline]
  55. Dufourny B, Alblas J, van Teeffelen HA, et al. 1997 Mitogenic signaling of insulin-like growth factor I in MCF-7 human breast cancer cells requires phosphatidylinositol 3-kinase and is independent of mitogen-activated protein kinase. J Biol Chem. 272:31163–31171.[Abstract/Free Full Text]
  56. Ng ST, Zhou J, Adesanya OO, Wang J, LeRoith D, Bondy CA. 1998 Growth hormone treatment induces mammary gland hyperplasia in aging primates. Nature. 3:1141–1144.
  57. Tornell J, Carlsson B, Pohjanen P, Wennbo H, Rymo L, Isaksson O. 1992 High frequency of mammary adenocarcinomas in metallothionein promoter-human growth hormone transgenic mice created from two different strains of mice. J Steroid Biochem Mol Biol. 43:237–242.[CrossRef][Medline]
  58. Yang XF, Beamer WG, Huynh H, Pollak M. 1996 Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation. Cancer Res. 56:1509–1511.[Abstract]
  59. Colao A, Marzullo P, Ferone D, et al. 1998 Prostatic hyperplasia: an unknown feature of acromegaly. J Clin Endocrinol Metab. 83:775–779.[Abstract/Free Full Text]
  60. le Roux CW, Monson JP, Chew SL, Grossman AB, Besser GM, Jenkins PJ. 2000 Increased serum prostate specific antigen in acromegaly - a cross sectional study. J Endocrinol. 164(Suppl):128.
  61. Wolk A, Mantzoros CS, Andersson SO, et al. 1998 Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. J Natl Cancer Inst. 90:911–915.[Abstract/Free Full Text]
  62. Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami HO. 1997 Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer. 76:1115–1118.[Medline]
  63. Chan JM, Stampfer MJ, Giovannucci E, et al. 1998 Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 279:563–566.[Abstract/Free Full Text]
  64. Wright AD, Hill DM, Lowy C, Fraser TR. 1970 Mortality in acromegaly. Q J Med. 39:1–16.[Medline]
  65. Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. 1980 Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol (Oxf). 12:71–79.[Medline]
  66. Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. 1988 Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand. 223:327–335.[Medline]
  67. Ron E, Gridley G, Hrubec Z, Page W, Arora S, Fraumeni Jr JF. 1991 Acromegaly and gastrointestinal cancer [published erratum appears in Cancer 1992 Jan 15;69(2):549]. Cancer. 68:1673–1677.[Medline]
  68. Cheung NW, Boyages SC. 1997 Increased incidence of neoplasia in females with acromegaly. Clin Endocrinol (Oxf). 47:323–327.[CrossRef][Medline]
  69. Ituarte EM, Petrini J, Hershman JM. 1984 Acromegaly and colon cancer. Ann Intern Med. 101:627–628.[Medline]
  70. Brunner JE, Johnson CC, Zafar S, et al. 1990 Colon cancer and polyps in acromegaly: increased risk associated with family history of colon cancer. Clin Endocrinol (Oxf). 32:65–71.[Medline]
  71. Rex DK, Lehman GA, Ulbright TM, et al. 1993 Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am J Gastroenterol. 88:825–831.[Medline]
  72. Pines A, Rozen P, Ron E, Gilat T. 1985 Gastrointestinal tumors in acromegalic patients. Am J Gastroenterol. 80:266–269.[Medline]
  73. Ziel FH, Peters AL. 1988 Acromegaly and gastrointestinal adenocarcinomas. Ann Intern Med. 109:514–515.[Medline]
  74. Barzilay J, Heatley GJ, Cushing GW. 1991 Benign and malignant tumors in patients with acromegaly. Arch Intern Med. 151:1629–1632.[Abstract]