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Original Studies |
Department of Clinical and Molecular Endocrinology and Oncology, University Federico II (A.C., P.M., D.F., G.C., V.M., A.D.S., B.M., G.L.), and Emergency Unit, Ospedale Incurabili (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, Via S. Pansini 5, 80131 Naples, Italy.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Symptoms due to prostatic, seminal vesicle, and/or urethral disorders
or obstruction were experienced by neither acromegalics nor controls.
Digital rectal examination revealed no occurrence of prostatic nodules
or other abnormalities. Compared to healthy subjects, a remarkable
increase in transversal prostatic diameter and volume was observed in
acromegalics. In healthy subjects, prostate volume ranged from
15.1–21.8 mL, whereas in acromegalics it ranged from 21.8–41.8 mL.
Similarly, an increased median lobe was observed. In fact, the
transitional zone diameter was just detectable in 5 of 10 controls,
whereas it was measurable in all acromegalics (18 ± 1.2
vs. 2.8 ± 0.3 mm; P < 0.001).
The prevalence of periurethral calcifications was more than doubled in
acromegalics (50%) compared to that in controls (20%). Treatment with
octreotide for 1 yr produced normalization of circulating GH and IGF-I
levels in 7 of 10 patients. In these 7 patients, ultrasound evaluation
showed a significant reduction of the antero-posterior diameter
(26.1 ± 1 vs. 28.9 ± 1.6 mm;
P < 0.01), the transversal diameter (44.9 ±
2 vs. 48 ± 2 mm; P < 0.01),
and the cranio-caudal diameter (36.5 ± 1 vs.
41.3 ± 1.5 mm; P < 0.001), whereas the
transitional zone diameter was unchanged (16.4 ± 1.5
vs. 17.4 ± 1.7 mm). As a consequence, a
significant decrease in prostate volume was recorded (22.1 ± 1.1
vs. 29.8 ± 2.5 mL; P <
0.001). Prostate volume increased in 2 of the 3 patients who did not
achieve normalization of GH and IGF-I after octreotide treatment.
Finally, after treatment, serum testosterone levels were significantly
increased (from 1.5 ± 0.3 to 3.5 ± 0.3 µg/L), whereas
dihydrotestosterone, dehydroepiandrosterone sulfate,
4-androstenedione, 17ß-estradiol, prostate-specific
antigen, and prostatic acid phosphatase were unchanged. Serum PRL
levels were suppressed after cabergoline treatment in all 4
hyperprolactinemic patients throughout the study period.
In conclusion, prostate enlargement occurs in young acromegalics with a higher than expected prevalence of micro- and macrocalcifications. This suggests that a careful prostate screening should be included in the work-up and follow-up of acromegalic males.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study was designed to investigate whether GH and IGF-I excess could lead to the development of benign prostatic hyperplasia and/or prostatic carcinoma in acromegalic patients. Prostatic diameters and volume as well as the occurrence of prostatic diseases were studied by ultrasonography in 10 untreated acromegalic patients less than 40 yr of age. Serum dihydrotestosterone (DHT) and prostate-specific antigen (PSA) levels were assessed to evaluate the participation of this regulatory factors in prostatic growth. After 1 yr of treatment with octreotide (OCT), ultrasound scan and hormone measurements were repeated to evaluate volume changes after suppression of GH/IGF-I levels had been achieved.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ten acromegalic patients, less than 40 yr of age (range,
26–39 yr), and 10 age- and body mass index-matched healthy males
entered this study after their informed consent had been obtained.
Acromegaly was diagnosed on the basis of clinical features, elevated GH
serum levels (36.9 ± 6.9 µg/L) not suppressible below 2 µg/L
by oral glucose administration, and elevated IGF-I plasma levels
(682.4 ± 67.4 µg/L). Four patients presented with coexistent
hyperprolactinemia (from 55.5–250 µg/L; Table 1
), whereas all patients suffered from
hypogonadism and showed reduced serum concentrations of FSH, LH (data
not shown), and testosterone (1.5 ± 0.3 µg/L; Table 1).
Computed tomography and/or magnetic resonance imaging documented the
presence of macroadenoma in 8 patients and microadenoma in 2 patients.
At study entry, 4 acromegalic patients and 4 control subjects were
smokers; none of the study subjects was a high alcohol consumer, and
all had normal diet intake. None of the patients who were included in
the study had previously received any androgen replacement therapy. The
patients’ profiles at study entry are shown in Tables 1 and 2.
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Circulating GH, IGF-I, PRL, FSH, LH, 17ß-estradiol,
testosterone, DHT, 4-androstenedione
(4), dehydroepiandrosterone sulfate (DHEA-S),
PSA, and prostatic acid phosphatase (PAP) were assessed at least twice
at study entry and quarterly during treatment with OCT. Ultrasound
examination was performed at study entry and after treatment with OCT.
All patients were treated with OCT (Sandostatina, Novartis, Milan,
Italy) for 1 yr. OCT was initially administered at a daily dose of 0.15
mg in six patients and 0.3 mg in four patients, according to patients’
compliance during the acute test (0.1 mg, sc), as previously reported
(5). Subsequently, the dose of 0.3 mg/day was maintained throughout the
follow-up in six patients, whereas it was increased up to 0.6 mg daily
in four patients to obtain GH/IGF-I suppression, improvement of
clinical signs and symptoms and/or tumor shrinkage. In the four
hyperprolactinemic acromegalics, a combined treatment with OCT plus
cabergoline (Dostinex, Pharmacia and Upjohn, Milan, Italy) at a dose of
1–2 mg/week was given to suppress serum PRL levels. At study entry,
plasma IGF-I levels were assayed twice in a single sample, whereas
serum GH was calculated as the mean of a 6-h blood sampling (0800–1400
h, 30-min sampling). During treatment, the final GH level was
calculated as the average value from at least three blood samples
collected at 15-min intervals 2 h after OCT administration. At
this time point, plasma IGF-I concentrations were assayed as single
sampling. Hormone normalization after OCT treatment was considered when
basal and oral glucose tolerance test-suppressed GH values were below 5
and 2 µg/L, respectively, and IGF-I values were within the normal
ranges.
Hormonal assessment
GH, PRL, testosterone, and 17ß-estradiol were measured by RIA;
IGF-I, FSH, LH, PSA, and DHT were determined by immunoradiometric
assay; PAP was measured by autoanalyzer. The normal ranges were: GH,
0–5 µg/L; IGF-I, 110–502 and 100–494 µg/L, respectively for
patients aged 20–30 and 31–40 yr; PRL, 5–15 µg/L; FSH and LH,
5–18 mU/mL; testosterone, 3.5–9 µg/L; DHT, 0.4–1.6 nmol/L;
4, 1–3.5 µg/L; DHEA-S, 60–560 µg/L;
17ß-estradiol, 20–70 µg/L; PAP, 0–2.6 U/L; and PSA, 0–10 µg/L.
All assessments were age adjusted.
Ultrasound examination
All of the patients received a preliminary enema with 120 mL
sodium acid phosphate (Clismalax, Sofar, Milan, Italy) not later than
1 h before the examination to favor rectal cleanliness. Before
ultrasonography, patients underwent a preliminary digital rectal
exploration. Prostate ultrasonography was carried out with ATL Apogee
800 (Advanced Technology Laboratories, Bothell, WA) by means of a
9.0-megahertz end-fire transrectal transducer (2-cm external diameter)
and a Power Echo Color Doppler Advanced Technology module that displays
the total integrated Doppler power in color, to obtain angiographic
micromaps (6). The transducer, preliminarily covered with ultrasound
transmission gel (Acquasonic, Parker Laboratory, Newark, NJ) and a
disposable rubber sheat, was lubricated and gradually inserted about 3
cm into the rectum, then directed toward the anterior rectal wall. The
following prostate diameters and features were evaluated in B-mode:
antero-posterior, transversal, cranio-caudal, and that including the
transitional zone (TZD); morphology of gland boundary; occurrence of
microcalcifications (
3 mm) and/or macrocalcifications (>3 mm);
detection and sizing of intraprostatic nodules; evaluation of seminal
vesicles; and occurrence of local inflammatory events. Reconstruction
by a standard ellipsoid formula (0.52 x length x
height x width) allowed the measurement of total prostate volume.
All scans were performed by a single examiner (S.S.). In agreement with
previous findings (7), normal prostate volume was considered as less
than 30 mL.
Statistical analysis
Data are expressed as the mean ± SEM. ANOVA, Student’s t test for paired data, and linear correlation analysis 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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), whereas FSH, LH, DHEA-S, 17ß-estradiol
(data not shown), DHT, PSA, and PAP (Table 1) were in the normal range.
All patients had secondary hypogonadism, as diagnosed by low
testosterone levels, and 4 of 10 patients had hyperprolactinemia (no.
2, 3, 5 and 6; Table 1). Ultrasonographic findings at study entry
Symptoms due to prostatic, seminal vesicle, and/or urethral
disorders or obstruction were not experienced by either acromegalics or
controls. Digital rectal examination revealed no occurrence of
prostatic nodules or other abnormalities. Compared to healthy subjects,
a remarkable increase in transversal diameter and volume of the
prostate gland was observed in acromegalics (Table 2). In healthy
subjects, prostate volume ranged from 15.1–21.8 mL, whereas in
acromegalics, it ranged from 21.8–41.8 mL. In 3 patients (no. 7–9;
Table 2), prostate volume was greater than 30 mL, which was considered
a normal threshold value (7). Similarly, an increased median lobe was
observed. In fact, TZD was just detectable in 5 of 10 controls, whereas
it was measurable in all acromegalics (18 ± 1.2 vs.
2.8 ± 0.3 mm; P < 0.001). The prevalence of
periurethral calcifications was more than doubled in acromegalics
(50%) compared to that in controls (20%; Table 2). Among the 10
acromegalics, calcifications in the periurethral zone were detected in
4 patients (no. 2, 3, 6, and 7), and calcifications within the lobes
were found in 1 patient (no. 1), whereas in another patient (no. 10) a
diffuse hyperechogenity of prostatic tissue with a single uthricolar
cyst was detected (Table 2). No sign of vesicle inflammation was shown.
No significant difference in prostatic volume (24.6 ± 1.5
vs. 31.1 ± 2.6 mL) or serum testosterone levels
(1 ± 0.4 vs. 1.9 ± 0.5 µg/L) was found between
hyperprolactinemic and normoprolactinemic acromegalics. A significant
correlation was found only between prostate volume and patient age
(Table 3).
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Treatment with OCT for 1 yr induced normalization of circulating
GH and IGF-I levels in 7 of 10 patients (Fig. 1). In these 7 patients, ultrasound
evaluation showed a significant reduction of antero-posterior diameter
(26.1 ± 1 vs. 28.9 ± 1.6 mm; P
< 0.01), transversal diameter (44.9 ± 2 vs. 48
± 2 mm; P < 0.01), and cranio-caudal diameter
(36.5 ± 1 vs. 41.3 ± 1.5 mm; P
< 0.001), whereas TZD was unchanged (16.4 ± 1.5 vs.
17.4 ± 1.7 mm). As a consequence, a significant decrease in
prostate volume was recorded (22.1 ± 1.1 vs. 29.8
± 2.5 mL; P < 0.001). The individual data of the 10
patients are shown in Fig. 1. Prostate volume increased in 2 (no. 3,
from 21.8 to 29.9 mL; no. 5, from 27.3 to 33.5 mL; Tables 1 and 2) of
the 3 patients who did not achieve normalization of GH and IGF-I after
OCT treatment (Fig. 1). In the remaining patient (no. 2), prostate
volume decreased from 27.3 to 20.5 mL despite evidence that GH
decreased from 65 to 11.3 µg/L, but was not normalized. In 1 patient
(no. 4) of the 7 who normalized GH and IGF-I levels after OCT
treatment, a hypoechoic nodular zone was detected within the left lobe
without a distinct boundary and with an irregular intralesional echoic
pattern (Fig. 2). The Power Echo Color
Doppler evaluation revealed high intra- and perilesional vascular flow.
Fine needle biopsy revealed nodular hyperplasia. After OCT treatment,
calcifications were still detected in the periurethral zone in 3
patients (no. 2, 5, and 6), whereas in 1 patient they disappeared.
Calcifications within the lobes were visualized in 2 other patients
(no. 4 and 8). In 2 patients, 1 presenting with single
macrocalcification within the right lobe (no. 1) and 1 with uthricular
cyst before therapy (no. 10), the examination performed 1 yr after OCT
treatment showed microcalcifications in the former and no further
detection of the cyst in the latter patient. Lastly, after OCT
treatment, serum testosterone levels were significantly increased (from
1.5 ± 0.3 to 3.5 ± 0.3 µg/L), whereas DHT, DHEA-S,
4, and 17ß-estradiol levels were unchanged.
In the 4 patients with hyperprolactinemia, serum PRL levels were
suppressed throughout the study (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase (12). A physiological decrease in testosterone in the
elderly seems to be followed by accumulation of DHT within the gland,
because of reduced catabolism and enhanced intracellular binding (12).
Therefore, different results of prostatic ultrasound evaluation in
older patients could not be excluded. Although the involvement of
several growth factors, such as PRL, epidermal growth factor,
fibroblast growth factor, and transforming growth factor- and -ß,
has been demonstrated both in vitro and in vivo
(13, 14), little is known about the direct involvement of GH in
prostate development. However, GH receptors have been demonstrated in
the rat prostate (15), and increased messenger ribonucleic acid
transcription for androgen receptors has been detected after GH and PRL
administration in immature rat prostate (16). The possibility that prostatic enlargement was actually due to the chronic excess of GH and IGF-I was supported by the significant decrease in prostate volume obtained after 1 yr of treatment with OCT in all patients who achieved GH/IGF-I suppression. As further support, in two of three acromegalics who did not achieve hormone suppression after OCT treatment, prostate volume was increased. As far as the prevalence of micro- and macrocalcifications was concerned, the 1-yr treatment with OCT led to the disappearance of microcalcifications and uthricular cyst in two patients, but caused the occurrence of microcalcifications in two other patients. On the basis of the detection of somatostatin receptors, primarily subtypes 1 and 2, in stromal cells of benign and malignant prostate (17, 18, 19), it is arguable that chronic OCT administration could regulate the GH/IGFs/IGF-binding protein paracrine-autocrine pathways within the gland. OCT could act on prostate size with different mechanisms. First, it can induce a decrease in prostate dimension by a direct antiproliferative effect (20) and indirectly by suppressing circulating levels of GH/IGF-I. Second, it may prevent prostate enlargement by inducing apoptotic processes of the mesenchymal tissue and by modifying the hemodynamics of local blood circulation (21). The positive effect of OCT treatment on prostate volume and morphology was observed despite a significant increase in testosterone levels and a significant improvement of spermatogenic activity (data not shown).
In conclusion, prostate enlargement occurs in young acromegalics with a higher than expected prevalence of micro- and macrocalcifications. These findings seem to be related to the GH/IGF-I excess, as they occur in the presence of evident hypogonadism. This suggests that a careful prostate screening, supported by transrectal ultrasound evaluation, should be included in the work-up of acromegalic males. Androgen replacement should be carefully monitored to avoid adding to prostate growth. Long term treatment with OCT can reverse prostate enlargement. The occurrence of micro- and macrocalcifications and even prostate nodules during OCT treatment indicates that monitoring of prostate size is also advisable in the follow-up of acromegalic patients.
Received September 10, 1997.
Revised November 21, 1997.
Accepted December 2, 1997.
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