Acromegaly and the Colon: Scoping Beyond the Pituitary

Abstract

Acromegaly is a complex endocrinological disorder commonly caused by hypersecretion of growth hormone (GH) typically due to pituitary gland tumors. Patients with acromegaly who are successfully treated and biochemically managed have a reasonably average life expectancy. However, it causes a cascade of multi-systemic involvement throughout the patient's life, including cardiovascular, neuropsychiatric, respiratory, metabolic, neurological, neoplastic, and gastrointestinal involvement, resulting in a higher rate of hospitalization, lower quality of life, and a shorter life expectancy. Although cardiovascular complications are the primary cause of death in patients with acromegaly, malignancy is now emerging as a major killer in these individuals. Colorectal carcinoma has been reported to be prevalent in acromegaly individuals. This review article has compiled studies to demonstrate a link between acromegaly and colorectal neoplasia, intending to provide a strong foundation for their clinical relationship. This article has summarised a potential pathogenic mechanism and provided insights into the clinical presentation of such patients. Furthermore, this article has provided a brief overview of current screening recommendations for colorectal neoplasia in acromegaly patients.

Full text

Review began 11/23/2021
Review ended 11/26/2021
Published 11/29/2021
© Copyright 2021
Patel et al. This is an open access article
distributed under the terms of the Creative
Commons Attribution License CC-BY 4.0.,
which permits unrestricted use, distribution,
and reproduction in any medium, provided
the original author and source are credited.
Acromegaly and the Colon: Scoping Beyond the
Pituitary
Gautami S. Patel , Idan Grossmann , Kevin Rodriguez , Mridul Soni , Pranay K. Joshi , Saawan C. Patel
, Devarashetty Shreya , Diana I. Zamora , Ibrahim Sange
1. Internal Medicine, Pramukhswami Medical College, Karamsad, IND 2. Research, Medical University of Silesia in
Katowice Faculty of Medical Sciences Katowice, Katowice, POL 3. Research, Universidad Americana (UAM) Facultad de
Medicina, Managua, NIC 4. Research, Shri Lal Bahadur Shastri Government Medical College, Mandi, IND 5. Research,
Department of Medicine, B.J. Medical College, Ahmedabad, IND 6. Medicine, Pramukhswami Medical College,
Karamsad, IND 7. Internal Medicine, Gandhi Medical College, Secunderabad, IND 8. General Medicine, Universidad de
Ciencias Médicas Andrés Vesalio Guzman, San José, CRI 9. Research, K. J. Somaiya Medical College, Mumbai, IND
Corresponding author: Gautami S. Patel, sonargautami2512@gmail.com
Abstract
Acromegaly is a complex endocrinological disorder commonly caused by hypersecretion of growth hormone
(GH) typically due to pituitary gland tumors. Patients with acromegaly who are successfully treated and
biochemically managed have a reasonably average life expectancy. However, it causes a cascade of multi-
systemic involvement throughout the patient’s life, including cardiovascular, neuropsychiatric, respiratory,
metabolic, neurological, neoplastic, and gastrointestinal involvement, resulting in a higher rate of
hospitalization, lower quality of life, and a shorter life expectancy. Although cardiovascular complications
are the primary cause of death in patients with acromegaly, malignancy is now emerging as a major killer in
these individuals. Colorectal carcinoma has been reported to be prevalent in acromegaly individuals. This
review article has compiled studies to demonstrate a link between acromegaly and colorectal neoplasia,
intending to provide a strong foundation for their clinical relationship. This article has summarised a
potential pathogenic mechanism and provided insights into the clinical presentation of such patients.
Furthermore, this article has provided a brief overview of current screening recommendations for colorectal
neoplasia in acromegaly patients.
Categories: Endocrinology/Diabetes/Metabolism, Internal Medicine, Gastroenterology
Keywords: growth hormone, insulin-like growth factor 1, colorectal carcinoma, colorectal polyps, acromegaly
Introduction And Background
Acromegaly is an endocrinological disorder characterized by an abnormally elevated growth hormone (GH)
level in the serum predominantly caused by a pituitary adenoma [1,2]. Pierre Marie, a French neurologist,
coined the term “acromegaly” to describe this disease’s morphological features [3]. It is a rare disease with
an incidence rate of 0.2 to 1.1 per 100,000 people and a prevalence rate ranging between 2.8 and 13.7 cases
per 100,000 people. Most patients are diagnosed in their 50s with an average diagnostic delay of 4.5-5
years [4]. Ninety-five percent of the cases are sporadic, and 50% of the cases are present in childhood as a
part of familial diseases such as familial isolated pituitary adenoma (FIPA), X linked acrogigantism (XLAG),
multiple endocrinal neoplasia-1 and 4 (MEN-1 and MEN-4), Carney complex, McCune-Albright syndrome,
neurofibromatosis or ‘3PAs’ syndrome [5]. When GH enters blood circulation, it signals the liver to produce
another hormone, called insulin-like growth factor-1 (IGF-1) which mediates many GH effects [6]. While
gigantism occurs due to excess GH levels before epiphyseal closure leading to an abnormal linear overgrowth
of bones, acromegaly manifests after the epiphyseal closure presenting with morphological features like
broad hands, feet, and fingers, wide and thick nasal bones, prominent zygomatic arch, bulging forehead
occasionally leading to frontal bossing, swollen lips with marked facial lines due to soft tissue thickening,
dental malocclusion due to mandibular overgrowth with prognathism along with maxillary widening leading
to tooth separation [6,7]. In addition, visual problems and headaches are believed to be due to the mass
effect of pituitary overgrowth [7]. Besides the musculoskeletal system, GH and IGF-1 have several systemic
manifestations, including cardiovascular, neuropsychiatric, respiratory, metabolic, neurological, neoplastic,
and gastrointestinal complications [7,8].
Although the clinical presentation of acromegaly is relatively apparent with regards to the physical
appearance of the patients, the workup usually begins with an elevated IGF-1 level as it is an indicator of GH
function. It is confirmed with an unsuppressed GH concentration after an oral glucose tolerance test (OGTT)
[9]. Radiological investigation such as magnetic resonance imaging (MRI) is often necessary to look for the
pituitary adenoma [9]. In certain rare clinical scenarios, Computed tomography (CT) scan of the thorax and
abdomen is done to localize towards an ectopic source of secretion of GH or growth hormone-releasing
hormone (GHRH) [10]. Even though transsphenoidal surgery is considered the mainstay of therapy, medical
management with drugs like octreotide (somatostatin analog), cabergoline (dopamine agonists),
pegvisomant (GH receptor antagonist) has been shown to help keep IGF-1 levels in the normal range [11-13].
Acromegaly is a complex disorder that manifests with multiple system involvement, out of which
1 2 3 4 5
6 7 8 9
Open Access Review
Article DOI: 10.7759/cureus.20018
How to cite this article
Patel G S, Grossmann I, Rodriguez K, et al. (November 29, 2021) Acromegaly and the Colon: Scoping Beyond the Pituitary. Cureus 13(11):
e20018. DOI 10.7759/cureus.20018

cardiovascular complications (congestive heart failure) are the main culprit behind the mortality in these
patients [14]. One of the lesser-explored areas in the subject of acromegaly is that of colonic involvement,
which can manifest with conditions such as colorectal polyps and carcinoma [15]. These conditions exhibit a
subtle clinical course. Most of them have an asymptomatic and insidious presentation, resulting in an
average of 12 years of delay in diagnosis [1]. This could result in the development of colon polyps and
possibly allow for pre-malignant lesions to transform into cancer, further amplifying the patient’s mortality.
This review article aims to: 1. Underline the pathogenesis and explore the clinical relationship between
acromegaly and the development of colonic complications; and 2. Emphasize the importance of early
screening and diagnosis of these conditions.
Review
Acromegaly and colorectal polyps
Acromegaly is most commonly caused by an anterior pituitary somatotrophic tumor that secretes GH, also
known as somatotropin [1]. GH is a protein hormone that binds to its membrane-bound growth hormone
receptor (GHR) on the liver [1,2]. Activated GHR, in turn, activates the enzyme Janus kinase 2 (JAK-2), a
cytoplasmic tyrosine kinase that phosphorylates tyrosine residues both within the JAK-2 enzyme and GHR
[1,2,16]. That serves as binding sites for a variety of signaling molecules leading to alteration of gene
expression [16]. As a result, the liver secretes IGF-1, also known as somatomedin, which binds to its receptor
on the colonic epithelium and serves its role (Figure 1) [1,2]. The amounts of insulin-like growth factor
binding protein-3 (IGFBP-3) and IGFBP protease in the blood affect the circulating levels of IGF-1. IGFBP-3
is produced by the liver alongside IGF-1 and works to inhibit IGF-1 activity by binding to it and lowering its
free levels [16]. Tissue produces IGFBP protease, which cleaves IGFBP-3, prevents its binding to IGF-1, and
balances the free IGF-1 levels [17]. The balance of all these three, IGF-1, IGFBP-3, and IGFBP protease,
determines free levels of IGF-1 in the blood (Figure 1) [18].
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 2 of 9

FIGURE 1: A summary of the possible pathogenesis of acromegaly that
results in colorectal complications.
GH: Growth Hormone
IGFBP-3: Insulin-like Growth Factor Binding Protein-3
IGF-1: Insulin-like Growth Factor-1
Since IGF-1 receptors are expressed in both normal and malignant colorectal epithelia, when activated by
IGF-1, the receptor-ligand complex suppresses apoptosis and enables progression through the cell cycle by
activating signal transduction pathways critical for cell growth and survival (Figure 1) [17,19,20]. Extensive
epithelial proliferation and a wide zone of proliferation found in the colon of acromegalic patients are
related to the levels of GH and IGF-1 [21]. As a result, IGF-1 has the ability to affect both pre-malignant and
neoplastic phases. Furthermore, IGF-1 stimulates the synthesis of vascular endothelial growth factor, an
angiogenic agent that promotes the development of blood vessels to support the colon cancer cell lines
(Figure 1) [22]. Additionally, IGF-1 receptors are upregulated in the colon of acromegaly patients, which is
vital to the survival of the mutated cells, giving legitimacy to the link between the IGF axis and neoplasia
[23]. Above mentioned might be one of the probable pathogenic mechanisms by which IGF-1 contributes to
the development and maintenance of colonic polyps in acromegaly patients.
Gonzalez et al. conducted a case-control nested in a cohort study in 2017 further to support this putative
function of IGF-1 in polyp development. The study revealed that high IGF-1 levels are significantly related to
the formation of colonic polyps, indicating that acromegaly patients are at a high risk of acquiring colonic
polyps [24]. Since colonic polyps can cause various abdominal symptoms, identifying individuals solely
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 3 of 9

based on their clinical presentation can be challenging. Wei et al. conducted retrospective research at
Beijing children’s hospital to determine the incidence of colon polyp symptoms in 487 patients. The study
discovered that rectal bleeding was the most common symptom in most patients, with additional symptoms
such as stomach discomfort, polyp protrusion from the anus, anemia, and diarrhea occurring in a few with
the common site of polyps being the rectosigmoid colon, and the number of polyps being single or multiple
[25]. However, in patients with acromegaly, colonic polyps could present somewhat differently. A study done
in 2020 by Inayet et al. suggested that the most cited issue in patients with acromegaly is functional
constipation. Such abdominal symptoms in patients with acromegaly may serve as a red flag for the
physician, prompting him or her to suspect and begin screening [26].
Ochiai et al. published a case-control study in 2020 with 178 cases and 356 age and gender-matched
controls to investigate the incidence of colon polyps in acromegaly patients. Following colonoscopy, 66.8%
of acromegaly patients were discovered to have polyps, but only 24.2% of controls (healthy individuals) were
found to have polyps (p=0.001). Acromegalic patients exhibited a higher number and larger size of polyps.
The most prevalent location was the rectosigmoid area, indicating that individuals with acromegaly are at an
increased risk of developing colorectal polyps than the general population (Table 1) [27]. In Turkey, Iliaz et
al. conducted a case-control study in 2018 with 134 acromegaly patients as cases and 134 age- and gender-
matched irritable bowel syndrome patients as controls. Following a colonoscopy and histopathological
examination, it was discovered that the acromegaly patients had a substantially greater incidence of all
types of colonic polyps (p=0.012). Histopathological examination revealed a higher incidence of hyperplastic
polyps (p=0.004), indicating that the incidence of hyperplastic polyps was increased in Turkish individuals
with active acromegaly (Table 1) [28]. Another study showed similar results as the studies mentioned above.
It was conducted in Poland in 2010 with 31 acromegaly patients with a mean age of 46.3 +/- 11.9 years.
Colon polyps were found in 13 individuals (41.9%) following colonoscopy. The results heavily suggested that
colon polyp frequency was linked to the duration of uncontrolled acromegaly (p=0.01) (Table 1) [29]. It is
also worth mentioning that, apart from polyps, colonic diverticula have also been reported in patients with
acromegaly, which can be explained by high IGF-1 levels in these patients [30].
Reference Design Population Method Diagnostic
modality Results Conclusion
Ochiai et al.
(2020) [27]
Retrospective
matched
case control
Patients with
acromegaly diagnosed
between april 2008
and september 2016
in toranomon hospital,
Japan.
Cases-178
Controls-
356
(Matched for
age and
gender)
Colonoscopy
66.8% of cases and 24.2% (p=
0.001) of controls were found
to have polyps. The size and
number were larger in the
acromegaly (case) group.
Patients with
acromegaly are at
greater risk of
developing
colorectal polyps.
Iliaz et al.
(2018) [28]
Case control
study Turkey
Cases-134
Controls-
134
Colonoscopy
followed by
histopathological
examination
The incidence of polyps in the
acromegaly group was higher
(p= 0.012) with an enhanced
incidence of hyperplastic
polyps (p= 0.004).
Turkish people with
acromegaly had a
higher incidence of
hyperplastic polyps.
Krzentowska et
al. (2010)
[29]
Poland
Total
patients-31.
Mean age-
46.3 +/- 11.9
years
Colonoscopy 13 individuals (41.9%) were
found to have polyps.
The length of
uncontrolled
acromegaly plays a
role in the
development of
colon polyps (p=
0.01)
TABLE 1: Summary of included studies revealing a clinical correlation between acromegaly and
colorectal polyps
These studies give compelling evidence for a favorable clinical relationship between acromegaly and
colorectal polyps. Colonoscopy and CT colonography are the two screening modalities. Once detected,
polyps are very well treated with endoscopic management modalities such as polypectomy, endoscopic
submucosal dissection (ESD), and endoscopic mucosal resection (EMR) if detected at an early stage.
Endoscopic management modalities are used to treat polyps based on their size and histological features
[31]. Polyps less than 5mm in size are too tiny to be surgically removed; instead, a yearly colonoscopy for
three years is recommended [31,32]. They can potentially grow into life-threatening carcinoma if left
untreated for an extended period. With the use of regular screening, polyps can be detected earlier and
treated before developing into carcinomas.
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 4 of 9

Acromegaly and colorectal carcinoma
The IGF-1 axis plays a vital role in carcinogenesis by promoting cellular turnover, leading to the
accumulation of molecular alterations that influence colon carcinoma development [33]. Colon carcinoma
can also be driven by RAS protein mutations that lead to increased IGF-1 signal transduction pathway
activity, elevating gene expression and mitogenicity, promoting the adenoma-carcinoma sequence
[34,35]. Tripkovic et al. conducted a study and demonstrated that individuals with colon carcinoma had
elevated levels of circulating IGF-1 [36]. Zhang et al., on the other hand, conducted a similar study to
investigate the role of IGF-1 and its receptor (IGF1R) in colorectal carcinoma and discovered comparable
results that high circulating IGF1 levels and mucosal IGF1R expression may play a significant role in both
the formation and development of colorectal carcinoma and may encourage the growth and malignant
transformation of adenomatous polyps [37].
Battistone et al. recently published a case-control study that comprised 70 acromegaly patients and 128
healthy controls. Advanced neoplastic lesions were found in 22 (31.4%) of patients and nine (7.0%) of
controls (p=0.0001, odds ratio (OR): 6.06); advanced adenomas were found in 18 (27.3%) and nine (7.0%) of
patients and controls, respectively (p=0.0006, OR: 4.57), and colorectal carcinomas were discovered in four
(5.7%) and zero (0.0%) of patients and controls, respectively (p=0.0063), indicating that acromegaly patients
had a higher risk of developing colon cancer (Table 2) [38]. In 2018, Dal et al. published a cohort study and a
meta-analysis of the literature to reinforce the cohort research’s findings. The study tracked a cohort of 529
acromegaly patients from the date of diagnosis with acromegaly until the first occurrence of a cancer
diagnosis, death, emigration, or end of the study period, whichever came first, and discovered 81 cases of
various malignancies (standardized incidence ratio (SIR) 1.1; 95% confidence interval (CI): 0.9 to 1.4).
Colorectal cancer had a SIR of 1.4 (95% CI: 0.7 to 2.6). These results were backed up by a meta-analysis of 23
studies producing overall cancer SIR of 1.5 (95% CI: 1.2 to 1.8) with an increased SIR for colorectal cancer of
2.6 (95% CI: 1.7 to 4.0), showing modestly higher incidence rates in acromegaly patients, but it also
highlighted the possibility of selection bias in certain previous studies (Table 2) [39]. Terzolo et al. assessed
the SIRs of several kinds of cancer in acromegaly in 2017 using a multi-centered cohort analysis of 1512
acromegaly patients. After a 10-year follow-up, 124 individuals were diagnosed with cancer, with a
substantially higher incidence of colon cancer (SIR: 1.67; 95% CI: 1.07-2.58, p=0.022), demonstrating a
modest increase in cancer risk in acromegaly patients (Table 2) [40]. Wolinski et al. performed a case-control
study in 2016; 200 patients and 145 controls were used in the study. Colon cancer was found in four (2.0%)
of acromegaly patients and zero in the control group (p=0.14), suggesting a heightened risk of cancer in the
acromegaly group (Table 2) [41].
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 5 of 9

Reference
(year)
Design
Population Method Results Conclusion
Battistone
et al.
(2021) [38]
Case-
control
study
Patients with
acromegaly from
15 Buenos Aires
hospitals.
Cases- 70 Controls- 128 All of
them underwent colonoscopy
and histopathological
examination.
1.Advanced neoplastic lesions seen in:
Cases-22 (31.4%) Controls-nine (7.0%)
(p=0.0001, OR: 6.06) 2.Advanced
adenomas: Cases-18 (27.3%) Controls-
nine (7.0%) (p=0.0006, OR: 4.57)
3.Advanced carcinomas: Cases-four
(5.7%) Controls-zero (0.0%) (p=0.0063)
There is a
high risk of
colon
carcinoma in
acromegalic
patients.
Dal et al.
(2018) [39]
Cohort
study
Population
comprised the
cumulative
population of
Denmark.
Recruited data
from the Danish
National Patient
Registry.
A cohort of 529 patients of
acromegaly was followed from
the date of diagnosis with
acromegaly until the first
occurrence of a cancer
diagnosis, death, emigration, or
end of the study period,
whichever came first.
SIR for colorectal cancer: 1.4 (95% CI: 0.7
to 2.6)
The
elevated
incidence
rate of
colorectal
cancer in
acromegaly
patients.
Terzolo et
al. (2017)
[40]
Cohort
study Italy
Assessed SIR of colorectal
cancer in 1512 cases of
acromegaly who were followed
up for 10 years.
Incidence of colorectal cancer (SIR- 1.67;
95% CI: 1.07-2.58, p=0.022)
Risk of
colorectal
cancer in
acromegaly
patients is
moderately
elevated
Wolinski
al. (2016)
[41]
Case-
control
study
Cases- 200 Controls- 145 Colon cancer was found in four (2.0%)
cases and zero controls (p=0.14).
There is a
high risk of
colon
malignancy
in
acromegaly
patients.
TABLE 2: Summary of included studies revealing a clinical correlation between acromegaly and
colorectal carcinoma
OR: Odds Ratio
SIR: Standardized Incidence Ratio
CI: Confidence Interval
Kurimuto et al. conducted research in 2008 to investigate the prevalence of benign and malignant tumors in
individuals with acromegaly. A retrospective chart analysis was done on 140 patients with active acromegaly
who had visited an outpatient clinic (male/female 54/86, age 55 +/- 25-year, range 21-86). In 10 individuals,
colon cancer was discovered. In comparison to the general population, the SIRs for colon cancer in
acromegaly patients was 17.4 (95% CI: 4.74-44.55) for females and 19.0 (95% CI: 5.18-48.64) for males,
indicating a substantial risk of colon cancer in acromegaly patients [42]. In 2008, Rokkas et al. published a
meta-analysis assessing the probability of colorectal neoplasia in acromegaly patients. The
study analyzed nine trials that included 701 patients with acromegaly and 1573 controls. The pooled
findings revealed that individuals with acromegaly had an elevated risk of colon cancer (OR: 4.351; 95% CI:
1.533-12.354; Z=2.762, p=0.006), consistent with the higher risk of colorectal cancer reported by the research
mentioned above [43]. Terzolo et al. conducted a cross-sectional study with 235 acromegaly patients in Italy
in 2005. Acromegaly patients’ colonoscopic findings were compared to 233 individuals with nonspecific
symptoms. Ten patients (4.3%) and two control participants (0.9%) had carcinoma (OR: 4.9; range-1.1-22.4),
with a higher probability of colonic neoplasia occurring in younger acromegaly patients compared to age-
matched controls, implying that acromegaly carries a moderate but definite elevated risk of colonic cancer
that develops at a relatively young age than in the general population [44]. Matano et al. conducted a
comparative investigation and found a similar outcome. In 2005, 19 acromegaly patients (cases) and 76 age,
gender, and smoking status matched controls enrolled in the case-control study. The prevalence of cancer
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 6 of 9

was more significant in acromegaly patients than in controls (p=0.05, OR: 9.8), demonstrating a link between
acromegaly and colon carcinoma [45].
These findings provide convincing evidence for a favorable clinical connection between acromegaly and
colorectal carcinoma. Having stated that, screening for colon pathologies in acromegaly patients becomes
critical. The objectives of screening are to detect dysplasia before it advances to carcinoma, detect carcinoma
before clinical symptoms appear, and prevent it from metastasizing. Direct visualization screening using
colonoscopy and flexible sigmoidoscopy, and CT colonography are considered as more effective modalities
for identifying colon neoplasia [46]. Alternative stool-based screening procedures that are less effective, such
as fecal immunochemical testing and fecal occult blood tests, stool deoxyribonucleic acid (DNA) tests
combined with fecal immunochemical tests, are generally avoided in these people [47]. Screening
colonoscopy should not be postponed in individuals with acromegaly under the age of 45, which is the age at
which screening is suggested in the average-risk group according to the U.S. Preventive Services Task Force
(USPSTF) [48]. There is substantial agreement across endocrine scientific societies on needing a colonoscopy
when acromegaly is diagnosed [49-52]. Repeat colonoscopy should be performed every five years if a colonic
adenoma is discovered during screening and if acromegaly is not adequately biochemically managed. The
timeframe for repeat colonoscopy changes according to the levels of GH and IGF-1. Follow-up colonoscopy
should be conducted with stricter compliance in such patients than in the general population. On the other
hand, surveillance colonoscopy is recommended every 10 years when acromegaly is biochemically
controlled [47].
Limitations
Potential confounding factors for the development of colorectal neoplasia such as age, gender, insulin
resistance, circulating insulin levels, diabetes mellitus status, hypertension status, body mass index, high
fatty diet, family history, and geographical distribution have not been taken into account in all of the
studies presented.
Conclusions
According to the studies covered in this article, despite patients with acromegaly having significant
morphological alterations, the condition is also a causal factor for colorectal neoplasia such as colorectal
polyps and colorectal carcinoma. IGF-1 is responsible for the majority of the pathological changes that take
place in acromegaly. Keeping the aforementioned facts in mind, we attempted to emphasize colorectal
neoplasia in patients with acromegaly in this review article to raise awareness among physicians to begin
screening for colorectal neoplasia using direct visualization methods such as colonoscopy and CT
colonography at the moment the patient is diagnosed with acromegaly. When such pathologies are identified
at an early pre-malignant stage with the aid of screening methods, grave sequelae such as colonic carcinoma
can be prevented with effective management, which has the potential to improve the quality of life and
extend the life expectancy of acromegalic patients. We believe that this article can serve as a foundation for
researchers to delve deeper into colorectal complications of acromegaly and explore the pathophysiology of
this illness in depth. However, we believe that the link between acromegaly and colorectal neoplasia
requires further large-scale research studies to be conducted while keeping confounding variables in mind in
order to establish appropriate screening and management guidelines.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
References
1. Colao A, Grasso LF, Giustina A, Melmed S, Chanson P, Pereira AM, Pivonello R: Acromegaly. Nat Rev Dis
Primers. 2019, 5:20. 10.1038/s41572-019-0071-6
2. Petrossians P, Daly AF, Natchev E, et al.: Acromegaly at diagnosis in 3173 patients from the Liège
Acromegaly Survey (LAS) Database. Endocr Relat Cancer. 2017, 24:505-18. 10.1530/ERC-17-0253
3. de Herder WW: The history of acromegaly. Neuroendocrinology. 2016, 103:7-17. 10.1159/000371808
4. Lavrentaki A, Paluzzi A, Wass JA, Karavitaki N: Epidemiology of acromegaly: review of population studies .
Pituitary. 2017, 20:4-9. 10.1007/s11102-016-0754-x
5. Gadelha MR, Kasuki L, Korbonits M: The genetic background of acromegaly . Pituitary. 2017, 20:10-21.
10.1007/s11102-017-0789-7
6. Chanson P, Salenave S: Acromegaly. Orphanet J Rare Dis. 2008, 3:17. 10.1186/1750-1172-3-17
7. Vilar L, Vilar CF, Lyra R, Lyra R, Naves LA: Acromegaly: clinical features at diagnosis . Pituitary. 2017, 20:22-
32. 10.1007/s11102-016-0772-8
8. Melmed S: Medical progress: acromegaly. N Engl J Med. 2006, 355:2558-73. 10.1056/NEJMra062453
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 7 of 9

9. Katznelson L: Diagnosis and treatment of acromegaly . Growth Horm IGF Res. 2005, 15:S31-5.
10.1016/j.ghir.2005.06.007
10. Doga M, Bonadonna S, Burattin A, Giustina A: Ectopic secretion of growth hormone-releasing hormone
(GHRH) in neuroendocrine tumors: relevant clinical aspects. Ann Oncol. 2001, 2:89-94.
10.1093/annonc/12.suppl_2.s89
11. Melmed S, Bronstein MD, Chanson P, et al.: A consensus statement on acromegaly therapeutic outcomes .
Nat Rev Endocrinol. 2018, 14:552-61. 10.1038/s41574-018-0058-5
12. Campana C, Corica G, Nista F, et al.: Emerging drugs for the treatment of acromegaly . Expert Opin Emerg
Drugs. 2020, 25:409-17. 10.1080/14728214.2020.1819983
13. Cámara R, Venegas E, García-Arnés JA, et al.: Treatment adherence to pegvisomant in patients with
acromegaly in Spain: PEGASO study . Pituitary. 2019, 22:137-45. 10.1007/s11102-019-00943-1
14. Lombardi G, Galdiero M, Auriemma RS, Pivonello R, Colao A: Acromegaly and the cardiovascular system .
Neuroendocrinology. 2006, 83:211-7. 10.1159/000095530
15. Kasuki L, Rocha PD, Lamback EB, Gadelha MR: Determinants of morbidities and mortality in acromegaly .
Arch Endocrinol Metab. 2019, 63:630-7. 10.20945/2359-3997000000193
16. Rechler MM: Growth inhibition by insulin-like growth factor (IGF) binding protein-3--what's IGF got to do
with it?. Endocrinology. 1997, 138:2645-7. 10.1210/endo.138.7.5355
17. Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions . Endocr
Rev. 1995, 16:3-34. 10.1210/edrv-16-1-3
18. Giovannucci E: Insulin, insulin-like growth factors and colon cancer: a review of the evidence . J Nutr. 2001,
131:3109S-20S. 10.1093/jn/131.11.3109S
19. Guo YS, Narayan S, Yallampalli C, Singh P: Characterization of insulinlike growth factor I receptors in
human colon cancer. Gastroenterology. 1992, 102:1101-8.
20. Koenuma M, Yamori T, Tsuruo T: Insulin and insulin-like growth factor 1 stimulate proliferation of
metastatic variants of colon carcinoma 26. Jpn J Cancer Res. 1989, 80:51-8. 10.1111/j.1349-
7006.1989.tb02244.x
21. Cats A, Dullaart RP, Kleibeuker JH, Kuipers F, Sluiter WJ, Hardonk MJ, de Vries EG: Increased epithelial cell
proliferation in the colon of patients with acromegaly. Cancer Res. 1996, 56:523-6.
22. Warren RS, Yuan H, Matli MR, Ferrara N, Donner DB: Induction of vascular endothelial growth factor by
insulin-like growth factor 1 in colorectal carcinoma. J Biol Chem. 1996, 271:29483-8.
10.1074/jbc.271.46.29483
23. Baserga R: The insulin-like growth factor I receptor: a key to tumor growth? . Cancer Res. 1995, 55:249-52.
24. Gonzalez B, Vargas G, Mendoza V, Nava M, Rojas M, Mercado M: The prevalence of colonic polyps in
patients with acromegaly: a case-control, nested in a cohort colonoscopic study. Endocr Pract. 2017, 23:594-
9. 10.4158/EP161724.OR
25. Wei C, Dayong W, Liqun J, Xiaoman W, Yu W, Xiaohong Q: Colorectal polyps in children: a retrospective
study of clinical features and the value of ultrasonography in their diagnosis . J Pediatr Surg. 2012, 47:1853-
8. 10.1016/j.jpedsurg.2012.05.024
26. Inayet N, Hayat J, Bano G, Poullis A: Gastrointestinal symptoms in acromegaly: a case control study . World J
Gastrointest Pharmacol Ther. 2020, 11:17-24. 10.4292/wjgpt.v11.i2.17
27. Ochiai Y, Inoshita N, Iizuka T, Nishioka H, Yamada S, Kitagawa M, Hoteya S: Clinicopathological features of
colorectal polyps and risk of colorectal cancer in acromegaly. Eur J Endocrinol. 2020, 182:313-8.
10.1530/EJE-19-0813
28. Iliaz R, Dogansen SC, Tanrikulu S, et al.: Predictors of colonic pathologies in active acromegaly: single
tertiary center experience. Wien Klin Wochenschr. 2018, 130:511-6. 10.1007/s00508-018-1367-3
29. Krzentowska A, Gołkowski F, Bałdys-Waligórska A, Hubalewska-Dydejczyk A: [Gastrointestinal tract polyps
in acromegaly patients]. Przegl Lek. 2010, 67:1266-9.
30. Wassenaar MJ, Cazemier M, Biermasz NR, et al.: Acromegaly is associated with an increased prevalence of
colonic diverticula: a case-control study. J Clin Endocrinol Metab. 2010, 95:2073-9. 10.1210/jc.2009-1714
31. Tanaka S, Saitoh Y, Matsuda T, et al.: Evidence-based clinical practice guidelines for management of
colorectal polyps. J Gastroenterol. 2015, 50:252-60. 10.1007/s00535-014-1021-4
32. Onoue K, Yamada H, Miyazaki T: Natural history of colorectal diminutive polyps with 5 mm or less-
prospective study. J Gastrointest Cancer Screen. 2008, 46:729-34. 10.1111/den.12263
33. Vogelstein B, Fearon ER, Hamilton SR, et al.: Genetic alterations during colorectal-tumor development . N
Engl J Med. 1988, 319:525-32. 10.1056/NEJM198809013190901
34. Jhun BH, Meinkoth JL, Leitner JW, Draznin B, Olefsky JM: Insulin and insulin-like growth factor-I signal
transduction requires p21ras. J Biol Chem. 1994, 269:5699-704.
35. Bos JL: The ras gene family and human carcinogenesis . Mutat Res. 1988, 195:255-71. 10.1016/0165-
1110(88)90004-8
36. Tripkovic I, Tripkovic A, Strnad M, Capkun V, Zekan L: Role of insulin-like growth factor-1 in colon
cancerogenesis: a case-control study. Arch Med Res. 2007, 38:519-25. 10.1016/j.arcmed.2007.01.012
37. Zhang R, Xu GL, Li Y, et al.: The role of insulin-like growth factor 1 and its receptor in the formation and
development of colorectal carcinoma. J Int Med Res. 2013, 41:1228-35. 10.1177/0300060513487631
38. Battistone MF, Miragaya K, Rogozinski A, et al.: Increased risk of preneoplastic colonic lesions and
colorectal carcinoma in acromegaly: multicenter case-control study. Pituitary. 2021, 24:96-103.
10.1007/s11102-020-01090-8
39. Dal J, Leisner MZ, Hermansen K, et al.: Cancer incidence in patients with acromegaly: a cohort study and
meta-analysis of the literature . J Clin Endocrinol Metab. 2018, 103:2182-8. 10.1210/jc.2017-02457
40. Terzolo M, Reimondo G, Berchialla P, et al.: Acromegaly is associated with increased cancer risk: a survey in
Italy. Endocr Relat Cancer. 2017, 24:495-504. 10.1530/ERC-16-0553
41. Wolinski K, Stangierski A, Dyrda K, et al.: Risk of malignant neoplasms in acromegaly: a case-control study . J
Endocrinol Invest. 2017, 40:319-22. 10.1007/s40618-016-0565-y
42. Kurimoto M, Fukuda I, Hizuka N, Takano K: The prevalence of benign and malignant tumors in patients
with acromegaly at a single institute . Endocr J. 2008, 55:67-71. 10.1507/endocrj.k07e-010
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 8 of 9

43. Rokkas T, Pistiolas D, Sechopoulos P, Margantinis G, Koukoulis G: Risk of colorectal neoplasm in patients
with acromegaly: a meta-analysis. World J Gastroenterol. 2008, 14:3484-9. 10.3748/wjg.14.3484
44. Terzolo M, Reimondo G, Gasperi M, et al.: Colonoscopic screening and follow-up in patients with
acromegaly: a multicenter study in Italy. J Clin Endocrinol Metab. 2005, 90:84-90. 10.1210/jc.2004-0240
45. Matano Y, Okada T, Suzuki A, Yoneda T, Takeda Y, Mabuchi H: Risk of colorectal neoplasm in patients with
acromegaly and its relationship with serum growth hormone levels. Am J Gastroenterol. 2005, 100:1154-60.
10.1111/j.1572-0241.2005.40808.x
46. Pickhardt PJ, Hassan C, Halligan S, Marmo R: Colorectal cancer: CT colonography and colonoscopy for
detection--systematic review and meta-analysis. Radiology. 2011, 259:393-405. 10.1148/radiol.11101887
47. Terzolo M, Puglisi S, Reimondo G, Dimopoulou C, Stalla GK: Thyroid and colorectal cancer screening in
acromegaly patients: should it be different from that in the general population?. Eur J Endocrinol. 2020,
183:D1-D13. 10.1530/EJE-19-1009
48. Colorectal Cancer: Screening . (2021). Accessed: October 22, 2021:
https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/colorectal-cancer-screening.
49. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA: Acromegaly: an endocrine
society clinical practice guideline. J Clin Endocrinol Metab. 2014, 99:3933-51. 10.1210/jc.2014-2700
50. Giustina A, Barkan A, Beckers A, et al.: A consensus on the diagnosis and treatment of acromegaly
comorbidities: an update. J Clin Endocrinol Metab. 2020, 105:937-46. 10.1210/clinem/dgz096
51. Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK: American Association of Clinical
Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly-
2011 update: executive summary. Endocr Pract. 2011, 17:636-46. 10.4158/ep.17.4.636
52. Melmed S, Casanueva FF, Klibanski A, et al.: A consensus on the diagnosis and treatment of acromegaly
complications. Pituitary. 2013, 16:294-302. 10.1007/s11102-012-0420-x
2021 Patel et al. Cureus 13(11): e20018. DO I 10.7759/cureus.20018 9 of 9