Full text of DOI:10.1007/BF03343997

J. Endocrinol. Invest. 25: 240-245, 2002
Prevalence of thyroid diseases in patients with acromegaly:
results of an Italian Multi-center Study
M. Gasperi*, E. Martino*, L. Manetti*, M. Arosio**, S. Porretti**, G. Faglia**,
S. Mariotti***, A.M. Colao****, G. Lombardi****, R. Baldelli*****, F. Camanni******,
A. Liuzzi*******, and the Acromegaly Study Group of the Italian Society of Endocrinology1
*Department of Endocrinology, University of Pisa, Pisa; **Institute of Endocrinological Sciences,
Ospedale Maggiore IRCCS, University of Milan, Milan; ***Institute of Internal Medicine, University of
Cagliari, Cagliari; ****Department of Endocrinology and Clinical and Molecular Oncology, University of
Naples, Naples; *****Department of Clinical Sciences, Section of Endocrinology, La Sapienza University,
Rome; ******Department of Internal Medicine, Division of Endocrinology, University of Turin, Turin;
*******Division of Endocrinology, Ospedale San Giuseppe, IRCCS, Auxologic Italian Institute, Verbania, Italy
ABSTRACT. Acromegaly is frequently associated
with the presence of thyroid disorders, however the
exact prevalence is still controversial. An Italian
multicenter study was performed on 258 patients
with active acromegaly (high levels of IGF-I and lack
of suppression of serum GH levels below 2 μg/l af-
ter an OGTT). The control group was represented
by 150 patients affected by non-functioning and
PRL-secreting pituitary adenomas. Two hundred
and two out of 258 acromegalic patients (78%)
were affected by thyroid disorders with a signifi-
cantly higher prevalence with respect to the con-
trol group (27%, p<0.0001). One hundred and
three patients presented (39.9%) non-toxic nodu-
lar goiter, 46 (17.8%) non-toxic diffuse goiter, 37
(14.3%) toxic nodular goiter, 1 toxic diffuse goiter
(0.4%), 12 (4.6%) Hashimoto’s thyroiditis, 3 (1.2%)
thyroid cancer. Two patients presented a co-se-
creting TSH pituitary adenoma. Thirty-six patients
had been previously treated for various thyroid ab-
normalities. Among the 222 acromegalic patients
never treated for thyroid disorders thyroid ultra-
sonography was performed on 194 subjects. Thy-
roid volume in patients with thyroid abnormalities
was 28 17.5 ml (median 23) while it was 10.8 3.6
ml (median 10) in patients without thyroid disorders
(p<0.0001). Thyroid volume was correlated with the
estimated duration of acromegaly (r=0.7, p<000.1),
but not with age or with serum GH, IGF-I and TSH
concentrations. Thyroid volume was higher in
acromegalic patients than in the above control pop-
ulation (23.5 16.9 ml vs 13.9 12.8 ml, p<0.0001).
In 62 acromegalic patients 101 fine-needle biopsies
of thyroid nodules were performed; 7 nodules were
suspicious and the patients were submitted to thy-
roid surgery: papillary thyroid carcinoma was found
in 3 patients. In conclusion, in a large series of
acromegalic patients an increased prevalence of
thyroid disorders (78%), particularly non-toxic nodu-
lar goiter, has been observed. Thyroid volume, eval-
uated by ultrasonography, was correlated to the
estimated duration of acromegaly. Finally, the
prevalence of thyroid carcinoma was slightly in-
creased than in the general population.
(J. Endocrinol. Invest. 25: 240-245, 2002)
©2002, Editrice Kurtis
INTRODUCTION
1Acromegaly Study Group of the Italian Society of Endocrinology:
Department of Internal Medicine, Division of Endocrinology, University
of Turin (E. Ghigo, E. Ciccarelli, P. Razzore); Turin Orbassano (A. Angeli,
M. Terzolo); Department of Clinical Sciences, Division of Endocrinology,
La Sapienza University, Rome (G. Tamburrano); Ospedale Niguarda,
Division of Endocrinology, Milan (R. Cozzi); Department of Internal
Medicine, University of Modena and Reggio Emilia (A. Velardo) and
Ospedale Bentivoglio, Bologna (G. Meringolo); Department of Endo-
crinology, University of Pisa (I. Lupi, M. Genovesi), Italy.
The association between acromegaly and goiter
has long been recognized, but the evaluation of
thyroid disorders in the presence of GH and IGF-I
excess has provided conflicting results, since the
prevalence of thyroid abnormalities in acromegaly
ranged from 25 to 92% in different series (1-8).
These discrepancies may partially be explained by
differences in the assessment of thyroid volume
and prevalence of goiter in geographic areas with
different iodine intake (Table 1). The aims of the
present multi-center study were to investigate the
Key-words: Acromegaly, thyroid diseases, goiter, IGF-I, TSH.
Correspondence: Prof. Enio Martino, Dipartimento di Endocrinologia e
Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro, Uni-
versità di Pisa, Ospedale Cisanello, Via Paradisa, 2, 56124 Pisa, Italy.
E-mail: emartino@endoc.med.unipi.it
Accepted November 10, 2001.
240

M. Gasperi, E. Martino, L. Manetti, et al.
Table 1 - Literature data regarding the prevalence of thyroid disorders in acromegaly.
Ref.
Author
Year
No. of Sex (%) of
patients females
Prevalence
(%) of thyroid evaluation
disorders
Method
Correlation with Correlation with Iodine
activity of
duration of
disease
status
acromegaly
1
2
3
4
5
6
7
8
Nabarro
Miyakawa et al.
Wuster et al.
Arosio et al.
Junik et al.
1987
1988
1991
1997
1997
1997
1999
2000
256
17
80
68
39
37
48
28
48
53
53
63
46
43
55
61
57
11
82
71
76
87
92
87
78
78
Palpation
N.E.
N.E.
N.E.
Yes
N.E.
N.E.
No
N.E.
N.E.
Ultrasound Yes (GH and IGF-I)
Palpation
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Yes (GH)
N.E.
Deficiency
N.E.
Yes (GH)
Yes (IGF-I)
No
Deficiency
N.E.
Cheung et al.
Kasagi et al.
Cannavò et al.
Yes
No
N.E.
No
Deficiency
Gasperi et al. This study 258
No
Yes
Moderate-
normal
N.E.: not evaluated.
ther non-functioning (no.=44) or PRL-secreting pituitary adeno-
ma (no.=106). Diagnosis had been performed by common endo-
crinological and imaging techniques.
prevalence of goiter and other thyroid abnormali-
ties in a large population of acromegalic patients
residing in moderate-normal iodine intake areas
and to correlate clinical and metabolic features of
thyroid disorders to parameters of acromegaly.
Assay
Serum free T4 (FT4) and free T3 (FT3) were measured by RIA
(Lisophase Kits, Lab. Bouty, Sesto San Giovanni, Italy); serum ul-
trasensitive TSH by an ultrasensitive IRMA (Auto-Delfia Wallac,
Gaithersburg, MD, USA). Normal values were: FT4, 8.4-23.2 pmol/l
(6-18 pg/ml); FT3, 3.8-8.4 pmol/l (2.5-5.5 pg/ml); TSH, 0.4-3.7 mU/l.
Serum anti-thyroglobulin (TGAb) and anti-thyroperoxidase (TPOAb)
antibodies were determined by IRMA methods with commercial
kits [(Sorin Biomedica, Saluggia, Italy; normal values were respec-
tively: <50 U/ml and <10 U/ml)]. Serum GH concentration was
measured by IRMA (Nichols Institute Diagnostics, San Juan
Capistrano, CA, U.S.A.), with a sensitivity of 0.1 μg/l. The inter- and
intra-assay coefficients of variation were 5.1-7.5% and 2.6-5.4%,
respectively. Serum IGF-I was determined by RIA (Nichols Institute
Diagnostics, San Juan Capistrano, CA, U.S.A.), with a sensitivity of
0.1 μg/l. The normal ranges for serum IGF-I according to age were
182-780 μg/l at 16-24 yr, 90-492 μg/l at 25-50 yr and 71-290 μg/l
over 50 yr. The inter- and intra-assay coefficients of variation were
8.8-10.8% and 5.0-9.5%, respectively. Serum PRL concentration
was measured by AIA-PACK IFMA (Eurogenetic, Italy); the normal
range was <25 ng/ml for women and <13 ng/ml for men.
SUBJECTS AND METHODS
Subjects
Acromegalic patients were recruited through the cooperation of 9
endocrinological centers in Italy. The iodine intake in these areas
was moderate-normal, as documented by the measurement of uri-
nary iodine secretion which ranges from 50 to 110 μg/l, as previ-
ously reported (9). Diagnosis of acromegaly was based on
anamnestic, clinical and laboratory data. Active disease was de-
fined by the presence of increased IGF-I levels (with respect to nor-
mal values according to age) and by lack of suppression of GH lev-
els below 2 μg/l after an (75 g) OGTT (10-13). The presumptive
duration of active disease was estimated by each investigator us-
ing a standardized form taking in account anamnestic, clinical and
laboratory data, if available.
Two hundred and fifty-eight patients, 147 women (57%) and 111
men (43%), were enrolled in the study. Mean age ( SD) was 50 13
yr (range: 17-80 yr), with no statistical difference between genders
(women: 51 12 yr, range 17-78 yr, men: 48 13 yr, range 22-80
yr; p=NS). Two of the patients presented a TSH co-secreting ade-
noma: their data were not included in the statistical analysis.
When enrolled, 88 patients (34%) had been previously treated for
acromegaly, with persistence of active disease. Medical therapy
had been administered in 57 patients, either alone (30 patients), in
combination with surgery (17 patients), surgery plus radiotherapy (3
patients), or radiotherapy (7 patients). Twelve patients had been
treated only by surgery, 7 only by radiotherapy and 11 by surgery
and radiotherapy.
Thyroid ultrasonography
Thyroid ultrasound evaluation was performed by well-trained physi-
cians in each center by a real-time instrument (Esaote, Biomedica,
Florence, Italy) using a 7.5 MHz linear transducer. Thyroid volume
was calculated according to the formula of the ellipsoid model:
width x length x thickness x 0,52 for each lobe (14, 15); all the im-
ages were re-evaluated in one center in blind manner. Goiter was
defined when the thyroid volume was >13 ml for females and >18
ml in males, which are the corresponding upper normal limits (9).
Eleven patients had previously been submitted to thyroid surgery,
21 patients were under treatment with L-T4 and 4 with methima-
zole. Thus, 222 had never been treated for thyroid disorders.
The control group consisted of 150 patients (122 females and 28
males) with mean age of 48 15 (range: 13-85 yr) affected by ei-
Thyroid scintigraphy
Thyroid scintiscan was performed, after administration of
99mtechnetium pertechnetate or 131iodine as a tracer, using a
rectilinear scanner or a ꢀ-camera.
241

Thyroid diseases in acromegaly
Fine needle aspiration
patients did not differ in women (119/147: 81%)
and men (85/111: 77%). Mean age was higher in
patients with than in those without thyroid disor-
ders (51 12 yr, range 22-80 yr vs 45 13 yr, range:
17-76 yr; p<0.01). The prevalence of thyroid ab-
normalities in controls was borderline significantly
greater in women vs men (38/122 or 31% vs 3/28 or
11%, ꢁ2=3.8 p=0.05). There was no difference
found between age of controls with and without
thyroid disorders.
In the subset of 222 acromegalic patients never
treated for thyroid disorders ultrasound data were
available in 194 patients. Thyroid volume was
23.5 16.9 ml (median 21 ml, range 4-137 ml), with
no differences between 108 women (22.9 16.8 ml,
median 19 ml, range 4-103 ml) and 86 men
(24.2 17.1 ml, median 21 ml, range 6-137 ml). In
the 143 patients with thyroid abnormalities the vol-
ume was 28 17.5 ml (median 23 ml, range 4-137
ml), while in the 51 patients without thyroid abnor-
malities it was 10.8 3.6 ml (median 10 ml, range 5-
18 ml; p<0.0001). Thyroid volume was correlated
with the estimated duration of acromegaly (r=0.7,
p<0.0001) (Fig. 2) but not with the age of patients
(r=0.2). Serum GH levels were 25.3 29.1 ng/ml
(range 0.8-185 ng/ml) and IGF-I 752 349 ng/ml
(range 328-1999 ng/ml), with no correlation be-
tween either parameter and thyroid volume. In con-
trol subjects the thyroid volume was 13.9 12.8 ml
(median 9 ml, range 4-87 ml), significantly smaller
(p<0.0001) than that of acromegalic patients. In the
41 patients with thyroid disorders the mean volume
was 24.3 20 ml (median 20 ml, range 4-87 ml),
while in the 109 patients without thyroid disorders
Fine needle aspiration (FNA) was advised in all subjects with
nodular goiter and was performed in 62 patients with acrome-
galy and in 14 controls. FNA was usually advised when solid and
mixed nodules where larger than 1 cm and cold at scintiscan.
Statistical analysis
Statistical analysis was performed using Statview 4.0 for Ma-
cintosh. Results were expressed as the mean SD, median and
range. The Student’s unpaired t-test and the chi-square test (ꢁ2)
were used when indicated. Linear regression analysis was per-
formed to analyze the relation between thyroid volume and esti-
mated duration of active disease, serum GH, IGF-I and TSH values.
RESULTS
In the whole group of acromegalic patients thyroid
abnormalities were found in 202 out of 258 patients
(78%), including non-toxic nodular goiter (NNG) in
103 patients, non-toxic diffuse goiter (NDG) in 46,
toxic nodular goiter (TNG) in 37 patients with one
or more hot nodules shown by thyroid scintigraphy,
toxic diffuse goiter (TDG) in 1, Hashimoto’s thy-
roiditis (HT) in 12, and differentiated thyroid cancer
(DTC) in 3. In the control group thyroid abnormali-
ties were found in 41 out of 150 patients (27%), in-
cluding NNG in 20 patients, NDG in 6, TNG in 2,
TDG in 1, HT in 11, and DTC in 1. The prevalence
of thyroid disorders in acromegaly was statistically
significant with respect to the control group
(p<0.0001, ꢁ2=100.1). Similarly the prevalence of
NNG, NDG and TNG was significantly higher in
acromegalic patients than in the control group but
not in HT, TDG and thyroid carcinoma (Fig. 1). The
prevalence of thyroid abnormalities in acromegalic
p<0.0001
Acromegalic patients
Control group
ꢁ2=100.1
100
80
60
40
20
0
78
27
p<0.0001
ꢁ2=30.5
50
40
30
20
10
0
39.9
p<0.0001
ꢁ2=15
p<0.0001
ꢁ2=17
17.8
p=NS
14.3
1.3
13.3
Fig. 1 - Prevalence of thyroid diseases
in 258 acromegalic patients and in the
control group (106 PRL-secreting pitu-
itary adenomas and 44 non-functioning
pituitary adenomas).
p=NS
1.2
p=NS
0.7
7.3
4.6
4
0.3
0.4
Non-toxic
Non-toxic
Toxic
Toxic
Hashimoto’s
thyroiditis
Thyroid
carcinoma
nodular goiter diffuse goiter nodular goiter diffuse goiter
242

M. Gasperi, E. Martino, L. Manetti, et al.
it was 10 4.6 ml (median 9 ml, range 4-18 ml;
p<0.0001).
performed in 14 patients: in 1 case there was a sus-
picion of PTC that was confirmed at surgery, while
in the remaining 20, 12 were benign, 4 cysts and 4
not diagnostic.
Serum thyroid hormones levels in 222 acromegalic
patients untreated for thyroid disorders were
11.5 5 pg/ml (range 5-60 pg/ml) for FT4 and
3.4 1.4 pg/ml (range 1.2-15 pg/ml) for FT3. Serum
TSH averaged 1.1 1 mU/l (range 0-9 mU/l); no cor-
relation was found with the estimated duration of
acromegaly (FT4: r=0.2; FT3: r=0.2; TSH: r=0.02).
TSH was not correlated with thyroid volume as well.
TGAb and TPOAb were positive in 21 and 23% of
patients, respectively. Serum thyroid hormones lev-
els in 150 control subjects were 10.3 3 pg/ml
(range 2-20.1 pg/ml) for FT4 and 3.2 0.8 pg/ml
(range 1.7-6.6 pg/ml) for FT3. Serum TSH averaged
1.3 1 mU/l (range 0-9mU/l). TGAb and TPO Ab
were positive in 26 and 21% of controls, respec-
tively.
In 62 patients 101 FNA of thyroid cold nodules
were performed: 56 were benign nodules, 30 cysts,
7 suspicious nodules (belonging to 7 different pa-
tients), while the procedures were not diagnostic in
8 cases. Of the 7 suspicious samples, 2 showed mi-
crofollicular architecture, 2 contained Hurthle cells,
2 had cellular abnormalities and one was suggestive
for thyroid carcinoma. Estimated duration of dis-
ease in these 7 patients was highly variable, rang-
ing from 48 to 300 months. All the patients with a
suspicious nodule underwent thyroid surgery. In 3
patients diagnosis of papillary thyroid carcinoma
(PTC) was confirmed (estimated duration of disease
was 48, 120 and 300 months), while in 4 micro-
macrofollicular goiter was diagnosed. Thus, 3 out
of 93 nodules with diagnostic results (3.2%) were
found to be PTC. In the control group 21 FNA were
DISCUSSION
The occurrence of goiter in acromegaly has long
been recognized (1-3). Differences in the reported
prevalence (ranging from 25 to 92%) may be relat-
ed to variations in the definition and assessment of
thyroid disorders (1-8). The apparent increased
prevalence recently observed can be attributed to
the use of highly sensitive thyroid ultrasonography.
Cheung and Boyages (6) detected thyroid en-
largement by ultrasound in 92% of 37 acromegalic
patients, with higher prevalence of nodular disease
in acromegaly of long duration. They also report-
ed that patients adequately treated for acromegaly
(normal serum IGF-I levels) tended to have smaller
thyroid glands than those with active acromegaly,
suggesting that goiter may partially be reversible
with the control of GH/IGF-I excess (6). Our study in
a large population of active acromegalic patients
confirms the high prevalence (78%) of various thy-
roid disorders, much higher than in a control pop-
ulation consisting of patients affected by non-se-
creting and PRL-secreting adenoma. This difference
was of particular relevance considering that: 1) in
the control group the female/male ratio was high-
er than in acromegalic patients; and 2) the preva-
lence of thyroid disorders is usually much higher in
females.
Goiter was by far the most frequent disorder, be-
ing present with its different expression (non-toxic
vs toxic) in 91% of acromegalic patients with thy-
roid abnormalities. The observed prevalence was
significantly higher than that found in the control
population consisting of patients affected by PRL-
secreting and non-functioning pituitary adenomas
(27%). In our study, patients with thyroid disorders
tended to be older, confirming what was observed
in a recent survey carried out in a Southern Italian
village located in a iodine-deficient area which had
never been submitted to a iodine prophylaxis pro-
gram. The study demonstrated that the prevalence
of goiter progressively increased with age, being
16% in children and 60% in adults (9). In our acro-
megalic patients no influence of gender could be
demonstrated in the development of thyroid dis-
orders, at variance with the observation of a high-
er prevalence of goiter in women, at least in iodine-
sufficient areas (16).
r=0.7; p=<0.0001
140
120
100
80
60
40
20
0
0
100
200
300
400
Estimated duration of active acromegaly (months)
Fig. 2 - Correlation between thyroid volume and estimated du-
ration of disease in a large group of acromegalic patients stud-
ied in 9 centers throughout Italy.
The mechanisms underlying the development of
goiter are not completely understood. It is well
243

Thyroid diseases in acromegaly
known that IGF-I potentiates the TSH-induced thy-
roid cellular growth in different cells systems in vi-
tro, such as FRTL-5 cells (17) or human normal thy-
roid cells (18). In addition, the mitotic response of
the thyroid gland to TSH is lost in rats after hy-
pophysectomy, but can at least partially be restored
by the administration of pituitary extracts (19). On
the other hand, the crucial role of TSH is demon-
strated by the inability of GH treatment to induce
any change in thyroid volume in GH and TSH-defi-
cient patients (20).
(mainly females) had biochemical, clinical and echo-
graphic signs of HT. Like in iodine-deficient areas (9,
28, 29), also in acromegaly an increased presenta-
tion of thyroid antigens to the immune system may
be a key factor in the activation of humoral and cell-
mediated immune reactions.
Three of 145 acromegalic patients with thyroid nod-
ules had thyroid cancer (2%). This figure is in agree-
ment with the expected prevalence of thyroid can-
cer in nodule-bearing non-acromegalic patients (30)
and similar to that found in control subjects, but is
somewhat higher if we consider the limited pro-
portion (43%) submitted to fine-needle thyroid
biopsy. On the other hand, the association between
acromegaly and neoplasia of various organs has
widely been recognized (31-34) and many experi-
mental data lend support to a possible tumorigenic
action of GH/IGF-I on thyroid cells: IGF-I receptors
were found to be present in neoplastic human thy-
roid tissues (35).
In conclusion, this multi-center study carried out in
a large series of acromegalic patients confirmed the
increased prevalence of thyroid disorders, particu-
larly in non-toxic goiter. Thyroid volume, as evalu-
ated by ultrasound, is not correlated to circulating
levels of GH and/or IGF-I, but shows a good corre-
lation with estimated duration of disease. Attention
should be paid in the diagnosis and follow-up of
thyroid abnormalities in acromegalic patients, par-
ticularly concerning thyroid nodules for the proba-
bility to find a thyroid carcinoma.
It has recently been demonstrated that TSH can in-
duce the expression of IGF-I mRNA in porcine thy-
roid follicles (21). Moreover, TSH induces a de-
crease in serum concentrations of different IGF-I
binding proteins (22), thus probably raising the
availability of free IGF-I (23). Then, it would appear
that both TSH and IGF-I might be part of a com-
plex network of signals contributing to modulate
and control thyroid cell growth and function (24).
At variance with some of the data from the litera-
ture (2, 6), but in accordance with others (5), data
regarding thyroid volume (estimated by ultrasound)
did not correlate with either serum GH or IGF-I lev-
els. These parameters, however, reflect the meta-
bolic situation at the time of sampling, but do not
reflect the disease history of the patient. Thus, it is
not surprising that, while no correlation was found
between these parameters and thyroid volume, a
positive correlation was demonstrated between thy-
roid volume and the estimated duration of disease.
At variance with Cheung and Boyages (6) and
Miyakawa et al. (2), we did not find any correlation
between thyroid volume and TSH, making it un-
likely that long-standing thyroid hyperstimulation
might result in thyroid autonomy, as suggested by
Cheung and Boyages. Our patients affected by tox-
ic goiter were not older nor had a longer duration
of acromegaly. Mutations in the TSH receptor or in
the Gs protein (Gsp)-ꢂ subunit have recently been
detected, leading to constitutive activation of the
TSH receptor-dependent adenylate cyclase cas-
cade, at least in a subset of toxic thyroid adenomas
and hyperfunctioning goiter nodules (25, 26). About
40% of acromegalic patients are bearing Gsp pos-
itive pituitary adenomas (27); it would be of interest
to investigate the distribution of Gsp-mutation
among pituitary adenomas and thyroid nodules,
and it seems reasonable to postulate their involve-
ment in the genesis of functional autonomy.
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