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Original Studies |
Department of Clinical and Molecular Endocrinology and Oncology, Federico II University of Naples (A.C., P.M., D.F., A.G., G.C., R.P., C.D.S., G.L.), and Emergency Unit, Incurabili Hospital Naples (S.S.), 80131 Naples Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, University Federico II of Naples, Via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it
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Abstract |
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30
mL) was found in 58% of the acromegalics and 26.6% of the controls.
When grouped by age (<40, 40–60, and >60 yr), PV was increased in
elderly patients compared to younger patients (P <
0.05) and to controls (P < 0.01). The prevalence
of structural abnormalities, including calcifications, nodules, cysts,
and vesicle inflammation, was significantly increased in patients
compared to controls (78.2% vs. 23.3%;
2 = 5.856; P < 0.05). No clinical,
transrectal ultrasonography, or cytological evidence of prostate cancer
was detected in acromegalic or control subjects. In conclusion, chronic
excess of GH and IGF-I cause prostate overgrowth and further phenomena
of rearrangement, but not prostate cancer. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reduced metabolite, dihydrotestosterone (DHT),
which seem to be the leading factors in stimulating its benign and
malignant disorders (1). The evidence that low testosterone levels do
not exclude occult prostate carcinoma (2) and that the growth factor
superfamily might regulate prostate tissue sheds new light on the role
that insulin-like growth factor I and II (IGF-I and -II) and
IGF-binding proteins (IGFBPs) have in the prostate (3). Both IGFs have
direct mitogenic effects on several tissues, including normal and
tumoral prostate epithelial cells, and their implication in prostate
cancer has been suggested as well (4, 5, 6). Conversely, IGFBP-2 and
IGFBP-3, the circulating carrier of IGF-I, are not unequivocally
considered to be involved in prostate growth in patients affected with
prostate cancer or benign prostate hyperplasia (7, 8, 9, 10). However,
IGFBP-3 can be cleaved by the prostate-specific antigen (PSA) contained
in the seminal plasma. In this way, the intraprostatic concentration of
IGF-I is increased (11). Moreover, IGF-I was found to be a significant
independent predictor of prostate cancer risk, whereas IGFBP-3 resulted
inversely correlated to the same risk (5). The implication of IGF-I in
promoting overgrowth of the prostate has been suggested by our recent
observation (12) in a group of young hypogonadic acromegalic patients,
in whom we did not expect to have age-dependent prostate diseases and
in whom we found a high prevalence of prostate disorders. To
better understand the possible regulatory role that GH and IGF-I play
in prostate pathophysiology, we investigated a large cohort of
acromegalic patients and control subjects and evaluated their prostate
dimensions, volume, and structural impairment by means of transrectal
ultrasonography (TRUS) and pituitary hormone, androgen, and prostate
hormone assay. We found a significant increase in prostate
disorders in acromegalic patients compared to the control population,
without any evidence of prostate cancer. |
Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Forty-six acromegalic males, aged 26–74 yr (mean ±
SEM, 50.5 ± 2.2 yr) were enrolled in this study; they
were free of previous or present prostate diseases and were not
receiving replacement treatment with androgen, -adrenergic
antagonists, or antiandrogen drugs. None of them had previously
experienced any episode suggesting prostate, gonadal, and/or urethral
disorders, such as prostatitis, orchitis, inflammation of seminal
vesicles, or spontaneous or precipitated acute urinary retention. The
study was performed after approval of the local ethical committee and
once the patients’ informed consents had been obtained. The diagnosis
of acromegaly was based on elevated GH levels not suppressible below 1
µg/L by oral glucose test, high IGF-I levels for age, signs and
symptoms of disease, and radiological evidence of pituitary adenoma. At
admission, 30 patients were in active disease (GH, 18.1 ± 2.5
µg/L; IGF-I, 531 ± 34 µg/L), whereas 16 had previously
undergone surgery and/or radiotherapy and were considered to be cured
on the basis of fasting GH below 2.5 µg/L or glucose suppressed below
1 µg/L and normal IGF-I for age (13). Ten of the 16 cured patients
had normal GH and IGF-I concentrations. The remaining 6 patients were
diagnosed as having severe GH deficiency (GHD) on the basis of a GH
response below 3 µg/L to a combined arginine plus GHRH stimulation
test (14); 4 of them were receiving replacement therapy with
L-T4, and 2 were receiving cortisone
acetate. As a control group, 30 healthy subjects were enrolled after
giving their informed consents and represented the age-matched
control-case subjects. The profiles of patients and controls at their
enrollment in our study are shown in Table 1
. The data obtained in the 76 subjects
were further analyzed according to age below 40 yr, between 41–60 yr,
and above 60 yr (Table 2a). Data obtained at
diagnosis from 10 patients less than 40 yr of age, previously reported
(12), were included in the present study. Eighteen acromegalics and 11
controls were smokers; no subject in either of the 2 groups was a heavy
alcohol drinker, and all consumed normal diets.
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The study protocol included hormonal tests performed using
commercially available kits and subsequently TRUS. Serum GH was
calculated as the mean of a 2-h blood sampling (0800–1000 h, with
every 30 min sampling). Circulating IGF-I, PRL, FSH, LH,
testosterone, DHT, sex hormone-binding globulin, 17ß-estradiol,
4-androstenedione, dehydroepiandrosterone sulfate, PSA,
free PSA, and PAP levels were assessed at least twice. The
cut-off values of 2.5 and 4 µg/L were considered the upper limits for
GH and PSA concentrations, respectively. The calculation of PSA
density, expressed as the ratio of PSA levels/prostate volume (PV) was
considered a risk factor for prostate cancer when it was higher than
0.15. All assessments were age adjusted. Serum GH levels were measured
by immunoradiometric assay. The sensitivity of the assay was 0.2
µg/L. The intra- and interassay coefficients of variation (CVs) were
4.5% and 7.9%, respectively. Plasma IGF-I was measured by
immunoradiometric assay after ethanol extraction. The sensitivity of
the assay was 0.8 µg/L. The intraassay CVs were 3.4%, 3.0%, and
1.5% for low, medium, and high points on the standard curve,
respectively. The interassay CVs were 8.2%, 1.5%, and 3.7% for low,
medium, and high points on the standard curve. Plasma IGFBP-3 was
measured by RIA after ethanol extraction. The sensitivity of the assay
was 0.5 µg/L. The intraassay CVs were 3.9%, 3.2%, and 1.8% for
low, medium, and high points on the standard curve, respectively. The
interassay CVs were 0.6%, 0.5%, and 1.6% for low, medium, and high
points on the standard curve.
Transrectal ultrasonography study
Before TRUS, all 76 subjects received a preliminary enema with 200 mL Sorbitole and a digital rectal exploration. TRUS was performed by means of an ATL Apogee 800 and a 9.0-MHz end-fire transrectal transducer with Power Echo Color Doppler module to display prostate angiographic micromaps (15). The transducer, preliminarily covered with ultrasound transmission gel (Acquasonic, Parker Laboratories, NJ) and a disposable rubber sheath, was lubricated and gradually inserted about 3 cm into the rectum, then directed toward the anterior rectal wall. The prostate examination covered the antero-posterior (APD), transversal (TD), and cranio-caudal (CCD) diameters; the transitional zone; the morphology of boundaries; the occurrence of calcifications and nodules; and the evaluation of seminal vesicles and of inflammatory events not previously reported by the patients. The PV and the volume of the transitional zone was calculated by means of the standard ellipsoid formula (0.52 x APD x TD x CCD). Echo-guided prostate biopsies with power Doppler enhancement were performed if clinical or hormonal conditions required it. All scans were performed by the same investigator (S.S.), who was blind in respect to patients’ disease activity. Prostate hyperplasia (PH) was considered for PV exceeding 30 mL, in line with the accepted criteria for benign prostate hyperplasia (16, 17).
Statistical analysis
Data are expressed as the mean ± SEM. ANOVA,
linear correlation analysis, and 2 test were applied
where appropriate. Statistical significance was set at 5%. Multiple
regression analysis was performed by considering PV and transitional
zone volume as dependent variables and the variables significantly
correlated at linear correlation as independent variables.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hormonal profiles of patients and controls are included in
Tables 1 and 2. Compared to controls, GH (P < 0.0001),
IGF-I (P < 0.0001), and IGFBP-3 (P <
0.001) levels were increased, whereas LH (P < 0.0001),
testosterone (P < 0.0001), and DHT (P
< 0.0001) levels were reduced in active acromegalic patients (Table 1
). Overt hypogonadism was present in 28 (60.8%) acromegalic patients
(20 untreated and 8 cured). When grouped by age, GH, IGF-I, and IGFBP-3
were significantly increased, whereas testosterone and DHT
significantly were decreased in patients compared to controls (Table
2). No difference in 4-androstenedione,
dehydroepiandrosterone sulfate, 17ß-estradiol, sex hormone-binding
globulin, PSA, free PSA, PSA density, or the ratio between free
PSA/PSA levels was found between patients and controls (Tables 1 and
2). PSA levels were elevated only in four and PSA density in three
patients, respectively. Six untreated patients had hyperprolactinemia
(serum PRL ranging from 16–550 µg/L).
Prostate dimensions (Tables 1 and 2)
TRUS showed an enlargement of APD, TD, and CCD in active
acromegalic patients compared to controls and GHD patients. No
difference was found in prostate diameters between controls and cured
non-GHD patients, except for a significant increase in the transversal
diameter in the latter group (P < 0.0001). The
transitional zone was detectable in 89% of acromegalic patients and in
66% of the controls. PV was greater in patients with active disease
than in cured non-GHD (P < 0.0001), GHD patients
(P < 0.0001), or controls (P <
0.0001; Table 1 and Fig. 1). The lowest
PV values (17.5 ± 1.1 mL) and IGF-I levels (182.3 ± 47
µg/L) were detected in the six acromegalic patients with GHD (Table 1
and Fig. 1). In active patients, PV was correlated with both age
(r = 0.668; P < 0.0001) and disease duration
(r = 0.626; P < 0.0001), and the multiple
regression model showed a greater dependence of PV on disease duration
(t = 3.297; P < 0.01) than on aging
(t = 2.689; P < 0.05). Conversely, no
significant correlation was found in the cured patients between PV and
disease duration. In the control group, PV and transitional zone volume
were directly correlated with age (r = 0.476; P <
0.01 and r = 0.763; P < 0.0001, respectively) and
were inversely correlated with IGF-I levels (r = -0.448 and
r = -0.550, P < 0.05, respectively). PH was
found in 24 of 30 active patients (80%), 3 of 10 cured non-GHD
patients (30%), none of the GHD patients, and 8 of 30 controls
(26.6%). PH prevalence was significantly associated with disease
activity (2 = 3.798; P < 0.05).
Grouping patients and controls by age, PH was recorded in 5 patients
(10.8%) and no controls less than 40 yr of age, in 11 patients (23%)
and 2 controls (6.6%) between 41–60 yr of age, and in 11 patients
(23%) and 6 controls (20%) more than 60 yr of age. As expected, the
highest PVs were recorded in acromegalic and control subjects above 60
yr of age, without any significant difference between them (Table 2 and
Fig. 2).
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The ultrasonographic signs of prostate abnormalities are
summarized in Table 2b. No abnormality of
prostate structure was detected in 10 of 46 patients (21.7%) or in 23
of 30 controls (76.6%). Calcifications were detected in 28 acromegalic
patients (60.8%) and 7 controls (23.3%): in the periurethral zone in
13 patients and 5 controls, within the lobes in 3 patients, and in the
zone immediately close to the transitional zone (peritransitional) in 3
patients and 2 controls. Concomitant periurethral/lobar calcifications
were observed in 5 patients and periurethral/peritransitional
calcifications were found in 4 patients. Uthricular cysts were found in
8 patients (17.4%), and in 2 cases were multiple, whereas cysts of the
verum montanum were found in 4 other patients (8.7%). Echoic signs
suggesting a condition of vesicles inflammation, including structural
impairment and/or calcifications, were observed in 4 patients (8.7%).
Clear-cut nodules were detected in 6 patients (13%); in 2 of them, 2
distinct nodules were detected. After echo-guided needle aspiration,
cytological examination was performed; it revealed nodular
fibroadenomatous hyperplasia in all cases. In addition, sextant
biopsies of the transitional zone were performed in 3 other patients
due to elevation of PSA levels and/or PSA density. In none of the
patients or controls was prostate cancer found. The prevalence of
prostate abnormalities was significantly associated with acromegaly
(2 = 5.856; P < 0.05).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the normal human, the endocrinology of prostate development depends
mainly on the stimulatory effect of testosterone and its 5-reduced
metabolite DHT throughout developmental and aging stages; castration or
pharmacological androgen deprivation notoriously cause impairment of
prostate growth (1). Nevertheless, androgens are supposed to act as
indirect factors, whereas cell to cell or stromal-epithelial
interactions might regulate the definitive development of the prostate
(1, 18, 19). A growing body of evidence is accumulating that IGFs may
be involved in prostate cell proliferation (3), but their actions still
need to be clarified. GH and its effector IGF-I, mainly carried in the
plasma by IGFBP-3, are physiological promoters of somatic growth,
although in vitro and in vivo studies have raised
the concern about whether they could also regulate hypertrophic and
tumoral proliferation of various tissues, including the prostate (3, 4, 5, 6, 20, 21, 22, 23). In fact, the expression of IGF-I and -II, IGF receptors, and
IGFBPs has been found in normal and tumoral prostatic tissue; in
vitro prostate cell growth is stimulated by IGF-I and inhibited by
IGFBP-3 (3, 8, 24, 25). Although GH and IGF-I excess has been reported
as being associated with an increased risk of developing cancer in
acromegaly (13, 26, 27), the increased growth effect on body organs and
bones predominates. In the 46 patients enrolled in this study, a more
than 3-fold prevalence of TRUS-documented prostate disorders was
observed compared to that in age-matched control subjects together with
a significant increase in PV in patients below 60 yr of age. Although
abnormality of the prostate structure was detected in 23% of controls,
in acromegalic patients calcifications were detected in 60.8%; cysts,
vesicle impairment, and/or benign nodules were found in 17.5% of
patients, accounting for a total prevalence of prostate abnormalities
in 78.3% of patients. The evidence that acromegalic patients either
cured or with GHD had normal or even decreased PVs further supports the
role of the GH/IGF-I axis in the pathophysiology of prostate growth.
The presence of prostate structural abnormalities in five of the six
GH-deficient patients is not surprising, as they might have developed
during the period of active disease. However, the risk of developing PH
increases with aging in both our control and acromegalic populations;
as a matter of fact, a significant correlation between PV and age was
found in both patients and controls. Furthermore, a significant
correlation was found between the thickening of the transitional zone
(detected in 89% of the acromegalics and in 20% of the controls) and
age. In the untreated patient group, PV was significantly correlated to
age and disease duration, and disease duration was the strongest
predictor of PH. By contrast, in the control group, PV was
significantly correlated with age and inversely with IGF-I levels; age
was the strongest predictor of PH.
The epidemiological peculiarity of our findings, however, cannot add further to reports of positive association between IGF-I levels and prostate cancer risk in normal men (5, 6, 28), which, far from being fully understood, ultimately suggest a predictor role for IGF-I levels in developing prostate cancer. Similar observations have been confirmed in females affected with breast cancer (29). In our series, despite chronic exposure to high IGF-I and IGFBP-3 concentrations, none of the patients was diagnosed as having prostate cancer. Therefore, it remains arguable whether IGF-I itself in the normal man could be a direct mitogen for tumoral proliferation. The possibility that IGF-I could be produced by the tumor itself or be implicated in a cause-effect phenomenon cannot be ruled out (3, 4, 5, 30). The evidence that a higher cancer risk is associated with lower IGFBP-3 levels, when adjusted to total IGF-I (5, 6), supports the possible modulatory role of free IGF-I bioavailability on prostate tissue.
It is intriguing that in acromegalic males, prostate diameters increased with aging, even with low androgen levels. Testosterone and DHT levels were significantly reduced in acromegalic patients, and 61% of them were clearly hypogonadic. Although adequate levels of androgens are necessary in early developmental stages, in the acromegalic male, prostate overgrowth seems to rely also on chronic GH and IGF-I excess, probably through the maintenance of proper cellular interactions.
In conclusion, the results of the present study show that chronically elevated GH, IGF-I, and IGFBP-3 levels determine prostate overgrowth and further phenomena of rearrangement, such as the increased prevalence of nodular lesions, calcifications, and cystic areas, but not cancer. However, as occult prostate cancer was found in 14% of men with low testosterone levels (2), the possibility of occult prostate cancer in patients not subjected to biopsy cannot be ruled out. It remains to be elucidated whether IGF-I itself might be implicated in the development of prostate cancer as a marker or, rather, whether the activities of different IGFBPs could regulate prostate cell proliferation.
Received November 30, 1998.
Revised February 26, 1999.
Accepted March 8, 1999.
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