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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., A.D.S., G.L.), and Emergency Unit, Santa Maria degli Incurabili Hospital (S.S.), 80131 Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Clinical and Molecular 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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After 2 yr, GH, IGF-I, and IGFBP-3 levels were decreased, whereas prostate-specific antigen levels did not change. PV was decreased in the 16 patients who were well controlled. Among the 6 patients with prostate hyperplasia at study entry who achieved disease control, 4 regained a normal PV at the end of the 2 yr of treatment, whereas none of the 5 patients with prostate hyperplasia at study entry and not achieving disease control normalized their PV. When patients were divided according to age, prostate volume decreased after 2 yr only in the 8 controlled patients aged below 50 yr, but not in those controlled and with age above 50 yr despite similar decrease in GH, IGF-I, and IGFBP3 levels. No clinical, transrectal ultrasonography, or cytological evidence of prostate cancer was detected during the study period. These data suggest that hyperplasia, but not cancer, is frequent in acromegalic men, and that the GH-IGF axis and age are independently associated with the development of this process.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The role played by the GH/IGF-I axis on prostate growth has also been suggested by our recent observations in acromegalic and GH-deficient patients. In fact, chronically elevated GH, IGF-I, and IGFBP-3 levels were shown to determine prostate overgrowth and structural changes, such as nodules, cysts, and calcifications, in a large proportion of acromegalic patients (13, 14), whereas in long-standing GH deficiency associated with hypogonadism, a decrease in prostate size was found (13, 15). Prostate hyperplasia was also found in young acromegalic patients, who were not expected to have age-dependent prostate diseases (13, 14). The evidence that prostate disorders occur in presence of hypogonadism and that prostate size decreases after 1 yr of treatment with octreotide in a small group of young patients (14), further supports the hypothesis that chronic GH/IGF-I excess causes prostate hyperplasia.
To better understand whether the control of GH and IGF-I excess by surgery and/or pharmacotherapy could reverse prostatic abnormalities in acromegaly, prostate volume as well as the occurrence of prostatic diseases were studied by transrectal ultrasonography (TRUS) in untreated patients before and 2 yr after treatment of acromegaly. The effects on the prostate were analyzed in patients achieving disease control and in those still presenting with disease activity at 2 yr.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-three acromegalic males, aged 29–70 yr (mean ±
sem, 50.0 ± 2.8 yr), were enrolled in this study; they were free
of previous or present prostate diseases and were not receiving
replacement treatment with androgen, ß-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 patients’ informed
consent had been obtained. The diagnosis of acromegaly was based on
elevated GH levels not suppressible below 3 mU/L by oral glucose test,
high IGF-I levels compared to age-matched controls, signs and symptoms
of acromegaly, and radiological evidence of pituitary adenoma (16, 17).
At admission, all patients were in active disease (GH, 117.9 ±
17.7 mU/L; IGF-I, 920.1 ± 60.8 µg/L). The profiles of the
patients’ at their enrollment in our study is shown in Table 1
. Ten patients were mild smokers; none
was a heavy alcohol drinker, and all consumed a normal diet. All
patients were included in a previous transversal study (13).
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The study protocol included hormonal tests and subsequently
TRUS. At diagnosis, serum GH was calculated as the mean of a 2-h blood
sampling (0800–1000 with 30-min sampling), whereas all of the other
hormone evaluations were performed in a single sample, as previously
reported (18). All patients except 3 underwent surgery, followed by
disease control in 9. In the remaining 14 patients, chronic treatment
with lanreotide (Ipstyl, Ipsen, Italy) was started at the initial dose
of 30 mg, im, every 14 days. The frequency of administration was
increased to every 10–7 days in 7 patients not achieving disease
control. A general clinic examination was carried out before and every
3 months during the follow-up. During treatment, the final GH level was
calculated as the average value from at least 3 blood samples collected
at 15-min intervals just before the next im injection of LAN (19). At
this time point, circulating IGF-I, IGFBP-3, PRL, testosterone (T),
dihydrotestosterone (DHT), 
4-androstenedione
(4), dehydroepiandrosterone sulfate
(DHEA-S), prostate-specific antigen (PSA), free PSA, and
prostatic alkaline phosphatase concentrations were assayed as single
sampling. Data were further analyzed according to patients less than or
more than (in 12 and 11) 50 yr of age. No patient received T
replacement.
Hormonal assessment
Circulating GH, IGF-I, PRL, FSH, LH, T, DHT,
4, DHEA-S, PSA, free PSA, and
prostatic alkaline phosphatase levels were assayed using commercially
available kits. The cut-off values of 7.5 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 (HGH-CTK-IRMA
Sorin, Saluggia, Italy). The sensitivity of the assay was 0.6 mU/L, 1
µg/L corresponds to 3 mU/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 using kits
from Diagnostic Systems Laboratories, Inc. (Webster, TX).
The sensitivity of the assay was 0.8 µg/L. The intraassay CVs were
3.4%, 3.0%, and 1.5% for the low, medium, and high points on the
standard curve, respectively. The interassay CVs were 8.2%, 1.5%, and
3.7% for the low, medium, and high points on the standard curve.
Plasma IGFBP-3 was measured by RIA after ethanol extraction using
kits from Diagnostic Systems Laboratories, Inc. The
sensitivity of the assay was 0.5 µg/L. The intraassay CVs were 3.9%,
3.2%, and 1.8% for the low, medium, and high points on the standard
curve, respectively. The interassay CVs were 0.6%, 0.5%, and 1.6%
for the low, medium, and high points on the standard curve.
TRUS study
Before TRUS, all 23 subjects received a preliminary enema with 200 mL sorbitol and a digital rectal exploration. TRUS was performed by means of an ATL Apogee 800 (Advanced Technology Laboratories, Bothell, WA) and a 9.0-MHz end-fire transrectal transducer with power echo color doppler module to display prostate angiographic micromaps (20). The transducer, preliminarily covered with ultrasound transmission gel (Acquasonic, Parker Laboratory, Newark, 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, transversal, and cranio-caudal diameters; the transitional zone; the morphology of boundaries; and the occurrence of calcifications and nodules. Seminal vesicles were imaged, and inflammatory events, not previously reported by the patients, were also investigated. The PV and the volume of the transitional zone were calculated by means of the standard ellipsoid formula (0.52 x antero-posterior diameter x transversal diameter x cranio-caudal diameter). 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 with respect to patients’ responses to treatment. Prostate hyperplasia was considered for PV exceeding 30 mL according to accepted criteria for benign prostate hyperplasia (21, 22).
Statistical analysis
Data are expressed as the mean ± SEM. ANOVA, followed by the Newman-Keuls test, and Student’s t test for paired data were applied where appropriate. Statistical significance was set at 5%.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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), and no abnormalities
in DHEA-S levels were found in any patient. None of the
patients had elevated PSA levels, whereas PSA density was high in 1
patient. Symptoms due to prostatic, seminal vesicle, and/or urethral
disorders or obstruction were not seen in any patient. Digital rectal
examination revealed no occurrence of prostatic nodules or other
abnormalities. Hormone and prostate characteristics before and after
treatment in the 23 patients are shown in Table 2. Prostate hyperplasia was found in 11
patients (no. 4, 8–10, 12, 13, 15, 18, 19, 22, and 23; Table 1).
Similarly, an increased median lobe was observed. In fact, the
transitional zone was measurable in all acromegalics, ranging from
1.3–25.8 mL (Table 2).
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and Table 3). Nine patients achieved disease
control by surgery alone, whereas the other 7 patients were treated
with 60–90 mg/month lanreotide, im, achieving sustained GH/IGF-I
suppression. Conversely, in the remaining 7 patients, GH and IGF-I
levels remained slightly elevated during the follow-up despite using
increasing doses of lanreotide (Table 3). In controlled patients, both
T and DHT levels were significantly increased compared to basal values
(Table 3), and among the 10 hypogonadal patients at study entry, 7
regained normal T and DHT levels. After 2 yr, the TRUS-measured
prostate size was significantly reduced compared to the baseline in
these 16 patients (P = 0.03; Table 3), whereas no
difference was found in 4,
DHEA-S, and PSA levels; PSA density; or the volume of the
transitional zone (Table 3). No difference in PV decrease was found
between patients controlled by surgery alone (from 38.3 ± 5.2 to
32 ± 3.7 mL) and those controlled by surgery and/or lanreotide or
lanreotide alone (from 25.8 ± 3.4 to 21.6 ± 2 mL). In these
2 subgroups, similar decreases in GH (Fig. 1), IGF-I (from 884.8
± 63.4 to 223.1 ± 41.1 and from 911.3 ± 113.8 to
236.0 ± 28.2 µg/L, respectively), and IGFBP-3 levels (from
5.7 ± 0.6 to 3.6 ± 0.4 and from 7.4 ± 0.7 to 4.2
± 0.6 mg/L, respectively) were found. Among the 16 controlled, 6
patients presented with prostate hyperplasia at diagnosis, 4 had a PV
of less than 30 mL at the end of the 2-yr follow-up (Fig. 1). In
contrast, no change in T and DHT levels or in whole prostate (Fig. 1)
and transitional zone volumes was observed in the 7 patients with
uncontrolled disease during the follow-up (Table 3). In particular,
hypogonadism and prostate hyperplasia, which were present in 3 and 5
patients at study entry, respectively, were not found in any of the
patients.
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). This was associated
with a decrease in IGF-I levels (Fig. 2), GH (from 111.3 ± 22.2
to 4.5 ± 1.2 mU/L; P = 0.002), and IGFBP-3 levels
(from 7.8 ± 0.6 to 4.7 ± 0.4 mg/L; P =
0.0002). In the 8 patients more than 50 yr of age, no significant
change in T and DHT levels or PV was observed despite similar decreases
in IGF-I levels (Fig. 2), GH (from
130.8 ± 46.2 to 3.6 ± 0.6 mU/L; P = 0.03)
and IGFBP-3 (from 5.2 ± 0.5 to 2.9 ± 0.3 mg/L;
P = 0.0001). Among the 7 uncontrolled patients, no
change was found in the dimension of the whole prostate and the
transitional zone in the 4 patients less than 50 yr of age (from
28.5 ± 3.9 to 35.7 ± 5.6 and from 4.4 ± 1.3 to
6.4 ± 1.7 mL) or in the remaining 3 more than 50 yr of age (from
71.3 ± 8.8 to 67.6 ± 11.9 and from 19.9 ± 3.1 to
20.6 ± 3.9 mL). However, it should be noted that elderly patients
with uncontrolled disease had the greatest size of whole prostate
(Figs. 1 and 3) and transitional zone at
study entry.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The pivotal role played by the chronic excess of GH and IGF-I in prostate overgrowth was also indicated by the significant decrease in PV obtained after 2 yr of treatment of the primary disease by surgery and/or lanreotide in the 16 patients who achieved successful GH/IGF-I suppression. As further support, in the 7 patients presenting with mild disease activity during the 2-yr follow-up, the levels of T and DHT and both the volume of the whole prostate and that of the transitional zone were unchanged. In the current series, the prevalence of cysts and micro- and macrocalcifications occurred in as many as 73.9% of the cases, confirming a previous report (13), and no significant changes in structural abnormalities of the prostate were found after 2 yr of treatment, at partial variance with a previous report (14). It should be mentioned, however, that our first study included only patients less than 40 yr of age. The age of the patients plays a relevant role when prostate dimensions and structure are investigated, as in humans prostate enlargement starts approximately at the age of 40 yr and rises from 23% to 88% by the ninth decade (26, 32). It is thus arguable that in elderly acromegalic patients prostate enlargement is due to both GH/IGF-I excess and the physiological age-related changes. On this basis, it is hard to expect a decrease in prostate dimension after suppression of GH/IGF-I levels in elderly patients. In fact, after 2 yr of treatment a significant decrease in prostate size was only found in well controlled patients less than 50 yr of age, not in those more than 50 yr, despite similar decreases in GH, IGF-I, and IGFBP-3 levels. In these controlled patients, a reduction in prostate volume was observed despite the significant increase in both T and DHT levels, confirming previous data obtained in another cohort of younger patients (14). In the small group of patients not achieving satisfactory disease control during the study period, however, no increase in prostate size was observed, and it should be noted that all 3 elderly patients in this group had very high prostate volumes at study entry. Together, these findings suggest that the possibility of documenting changes in prostate size and structure during a 2-yr period in subjects over 50 yr of age is unlikely.
With regard to the detection of somatostatin receptors, primarily subtypes 1 and 2, in stromal cells of benign and malignant prostate (33, 34, 35), it is arguable that the chronic lanreotide administration could regulate the paracrineautocrine pathways of the GH/IGF/IGFBP system within the gland. Lanreotide treatment can induce a decrease in prostate dimension by displaying a direct antiproliferative effect (36), by indirectly suppressing circulating levels of GH/IGF-I, or both. It should be mentioned that octreotide, another somatostatin analog, was used together with complete androgen blockade in patients with prostate carcinoma with beneficial results (37). Lanreotide treatment could also prevent prostate enlargement by inducing apoptosis of the mesenchymal tissue and by modifying the hemodynamic conditions of the local blood circulation (38). As the reduction in PV was also observed in patients achieving disease control by surgery alone, the possibility that GH and IGF-I suppression itself had a direct shrinking effect on the prostate is highly likely. Finally, in none of the patients were PSA levels, digital rectal exploration, or TRUS able to detect the occurrence of prostatic cancer in young/adult and elderly patients.
In conclusion, the prostate is a primary target tissue of GH and IGF-I. Chronic suppression of GH and IGF-I levels by surgery or lanreotide treatment induced a significant decrease in PV in the acromegalic patients achieving disease control, mostly in those less than 50 yr of age and thus not affected by age-dependent prostate hyperplasia. The inhibitory effect of GH and IGF-I suppression on prostate size was documented despite a significant increase in androgen levels. These data indicate that the GH/IGF-I axis plays a role in the development of prostate overgrowth in acromegaly; that it plays a similar role in nonacromegalic subjects cannot be ruled out.
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Acknowledgments |
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Footnotes |
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Received April 25, 2000.
Revised June 26, 2000.
Accepted June 29, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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