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Department of Clinical and Molecular Endocrinology and Oncology (A.C., G.V., A.D.S., E.G., A.C., G.L.), Federico II University of Naples; and Emergency Unit, S. Maria degli Incurabili Hospital (S.S.), Naples, 80131 Italy
Address all correspondence and requests for reprints to: Dr. Annamaria Colao, 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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Introduction |
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The in vitro experiments using cultured prostate explants (5, 6, 7) and cell lines (8) confirmed that exogenous PRL is able to stimulate the proliferation and secretion (5, 6) and to increase the survival (7) of prostate epithelium. Moreover, an enlargement of the dorsolateral prostate was shown in transgenic mice with overexpressed PRL (8), implicating PRL in growth of the prostate gland. Studies of prostatic PRL signaling pathways demonstrated the expression of PRL receptors (9, 10) and coupling of receptor activation, mainly to the Janus kinase 2-signal transducer and activator of transcription 5a/b pathway, but also to the Ras-MAPK pathway (11, 12).
Little is known, however, about the specific and direct effects of PRL on the human prostate, and the mechanisms underlying the responses of prostate cells to PRL remain unclear (1, 13, 14). In contrast, to date no consistent demonstration of the role of human PRL in prostatic disease (15, 16) or even in normal prostate function has been presented.
In this observational, open, prospective, case-control study we investigated the effects of hyperprolactinemia and its control by cabergoline, a dopamine receptor agonist subtype 2, on prostate structure in young men with prolactinoma.
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Subjects and Methods |
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From 1996–2000, 74 consecutive newly diagnosed men with hyperprolactinemia were admitted to our department and received cabergoline as primary treatment (17). Exclusion criteria for entering the prostate study were 1) previously experienced episode suggesting prostate and/or urethral disorders, such as prostatitis, orchitis, and inflammation of seminal vesicles, 2) spontaneous or precipitated acute urinary retention, 3) alcohol abuse, and 4) age greater than 55 yr, as we previously demonstrated a scant response in prostate size decrease in elderly patients despite an optimal control of acromegaly (18). All patients were proposed to receive a transrectal prostate ultrasonography, except for three who had experienced prostate disorders in their past history; 31 patients did not give their consent, and seven patients were excluded for age above 55 yr. The remaining 33 men entered the study after their informed consent had been obtained. To avoid interference from replacement therapies with testosterone and GH, both of which were shown to increase prostate size in hypopituitary men (19), data from 13 patients were subsequently excluded, because five did not achieve PRL normalization, four required testosterone replacement, and four required testosterone and GH replacement. Thus, in this pilot study were included results obtained for patients achieving control of hyperprolactinemia and normalization of testosterone levels during cabergoline treatment and not requiring GH or gonadotropin replacement throughout the study period. These were 20 men, aged 34 ± 10 yr (range, 20–55 yr), 16 with macroadenomas and four with microadenomas (Table 1
). Twenty healthy men, age-matched with the patients and fulfilling the inclusion criteria, agreed to serve as controls. The study was performed after approval of the local ethical committee. All 40 subjects gave their informed consent to the study.
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This is an observational, open, prospective, case-control study. At diagnosis, serum PRL levels were measured during a 2-h blood sampling (0800–1000 h with 30-min sampling), and the average value was calculated and used for statistical analysis (20). In the patients, PRL, testosterone, DHT, IGF-I, IGF-binding protein-3 (IGFBP-3), and prostate-specific antigen (PSA) levels were measured before and after 6, 12, and 24 months of cabergoline therapy, and transrectal ultrasonography (TRUS) of the prostate was performed before and after 12 and 24 months. In the controls, PRL, testosterone, PSA, and prostate TRUS were performed at study entry and after 24 months.
Treatment protocol
Cabergoline was the first line therapy for all patients. Based on the findings of previous studies (21, 22, 23), treatment was started orally at a dose of 0.5 mg once weekly for the first week, then was given twice weekly. Dose adjustment was carried out every 2 months on the basis of PRL suppression; the dose was increased when hormone levels were more than 15 µg/liter. In large macroprolactinomas showing an infrasellar extension, the starting dose of cabergoline was 0.25 mg once a week for the first week, then twice weekly to reduce the dosage below levels associated with risk of rhinorrhea (24). Dose adjustment was performed as described above. All patients were followed for 24 months. This series included only responsive patients, and the final median dose of cabergoline was 1 mg/wk (range, 1–2 mg/wk).
TRUS study
According with our protocol (18, 19, 25, 26), before TRUS, all 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. 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 prostate volume (PV) of the transitional zone was calculated by means of the standard ellipsoid formula (0.52 x antero-posterior x transversal x cranio-caudal). Echo-guided prostate biopsies with power Doppler enhancement were performed according to clinical or hormonal conditions. Prostate hyperplasia was considered for PV greater than 30 ml.
Assays
PSA levels were assayed using commercially available kits; 4 µg/liter is the upper limit of normal. The calculation of PSA density, expressed as the ratio of PSA levels/PV is considered a risk factor for prostate cancer when higher than 0.15 (24). All assessments were age-adjusted. Serum testosterone, DHT, and PRL levels were assayed using commercial kits. Normal ranges were: testosterone, 3–9 µg/liter; DHT, 0.4–1.6 nmol/liter; and PRL, 5–15 µg/liter. Plasma IGF-I was measured by immunoradiometric assay after ethanol extraction; the sensitivity of the assay was 0.8 µg/liter. The normal IGF-I range for men in our laboratory is 110–500 µg/liter in 20- to 30-yr-olds, 100–450 µg/liter in 31- to 40-yr-olds, 100–300 µg/liter in 41- to 50-yr-olds, and 90–270 µg/liter in 51- to 60-yr-old subjects. Plasma IGFBP-3 was measured by RIA after ethanol extraction; the sensitivity of the assay was 0.5 µg/liter. The normal IGFBP-3 range in our laboratory is 3.7–7.2 in 20- to 30-yr-olds, 2.7–6.5 in 30- to 40-yr-olds, 2.5–5.4 in 40- to 50-yr-olds, and 2.3–4.3 in 50- to 60-yr-old subjects. The kits for IGF-I and IGFBP-3 assays were purchased from Diagnostic System Laboratories, Inc. (Webster, TX).
Statistical analysis
Data are expressed as the mean ± SD. Kruskal-Wallis tes, followed by Dunn’s test, and the Wilcoxon matched paired tests were applied as appropriate. The correlation analysis was performed by calculating the Spearman coefficient. Statistical significance was set at 5%.
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Results |
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, lower serum testosterone, DHT, and IGF-I levels and PV and higher PRL levels and PSA density were higher in the patients than in the controls. Below normal values of testosterone, DHT, and IGF-I were found in 12, 12, and eight patients, respectively (Table 1
). None of the patients or controls had elevated PSA levels or PSA density; prostate hyperplasia was found in two controls (10%), but in none of the patients. Digital rectal examination revealed no occurrence of prostatic nodules or other abnormalities. Endocrine and prostate characteristics before treatment in the patients and controls are shown in Table 2. Individual values for PV and transition zone volume in patients and controls are shown in Fig. 1. To distinguish the effects on the prostate of hyperprolactinemia from those of hypoandrogenemia, patients were divided into those with abnormal (n = 12) and those with normal (n = 8) testosterone and DHT levels. There was no difference in PV (15.9 ± 2.8 vs. 14.7 ± 4.5 ml; P = 0.45; Fig. 2) and transitional zone volume (1.3 ± 1.0 vs. 0.5 ± 0.8 ml; P = 0.07) between patients with normo- and hypoandrogenemia. At study entry, PV was significantly correlated with age (r = 0.67; P = 0.0012), PSA levels (r = 0.57; P = 0.009), and transitional zone volume (r = 0.56; P = 0.001), but not with PRL, testosterone, DHT, IGF-I, or IGFBP-3 levels in the patient group. In controls, PV was significantly correlated with age (r = 0.64; P = 0.0024), testosterone (r = –0.86; P < 0.0001), IGF-I (r = –0.53; P = 0.01), and transition zone volume (r = 0.67; P = 0.0012). None of the patients presented structural abnormalities, such as calcifications, nodules, cysts, or vesicle inflammation; in one control (5%) a nodule was found that was negative for malignancy at biopsy.
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) had normalized testosterone and DHT levels (data not shown). After 12 and 24 months, PRL, testosterone, and DHT levels were normal in all cases, as were IGF-I and IGFBP-3. Mean values in the patient and control populations are shown in Table 3. A significant increase in PV and transitional volume (Table 3 and Fig. 1) was found during the study. After 24 months of cabergoline therapy, both PV and transitional zone volume were comparable to control values. There was no change in the increase in volumes of the entire prostate and the transitional zone between patients with hypoandrogenemia at study entry and those with normal androgen levels (Fig. 2). The percent increase in testosterone levels after 12 and 24 months was not correlated with the percent increase in prostate volume at both time points (r = 0.19; P = 0.41 and r = 0.03; P = 0.9). There were no changes in prostate structure throughout the study period in either the patients or the controls.
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Discussion |
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To date, no data on the effects of hyperprolactinemia on the prostate in patients with prolactinoma are available. Based on a wide literature in experimental models, hyperprolactinemia should induce prostate hypertrophy (1, 2, 3, 5, 6). PRL is expressed in rat and human prostate epithelium (6, 27), and thus the prostate, in analogy with other tissues, can directly process PRL by posttranslational glycosylation, phosphorylation, or proteolytic cleavage (28, 29) into molecular derivatives, with different cellular targets and biological activities. The level of locally produced prostatic PRL was demonstrated to be regulated by androgens (30). However, progressive prostate hyperplasia in adult PRL transgenic mice was reported to be independent of elevated serum androgen levels (31), and prolonged androgen treatment in adult wild-type male mice did not significantly affect prostate growth (31). A differentiation between PRL and androgen action on the prostate has been recently clarified by a new transgenic mouse model (probasin-PRL) (32). In this mouse line, PRL gene expression is targeted to the prostate with a prostate-specific probasin promoter without remarkable systemic effects, such as increased serum levels of PRL or androgens. The effects include stromal expansion, accumulation of inflammatory cells, ductal dilatation, and focal epithelial dysplasias, which all are considered basic characteristics of human benign prostatic hyperplasia (33).
These experimental findings were not supported by the results of the current study or by recent epidemiological data in men with prostate cancer. In fact, Stattin et al. (34) conducted a case-control study nested within the Northern Sweden Health and Disease Cohort using plasma samples collected from 29,560 men at a health survey. They measured serum PRL in the 144 men who had a diagnosis of prostate cancer after a median follow-up time of 4 yr after the health survey and from 289 controls matched for age and date of recruitment. Prostate cancer risk was not associated with PRL levels in univariate regression analysis, and odds ratios of prostate cancer for increasing quartiles of PRL were 1.0, 0.92, 0.82, and 0.85. Similarly, in our selected group of de novo men with prolactinoma, we found lower than normal prostate size at diagnosis as well as very high PRL levels. To investigate whether this effect was mediated by low androgen levels, we examined the effects of hyperprolactinemia and its control after cabergoline treatment, separately in patients with hypoandrogenemia and those starting with normal testosterone and DHT levels. PV and transitional zone volume were similar in both groups before and during therapy. However, even if eight patients with hyperprolactinemia had testosterone and DHT levels in the normal range, they had lower hormone levels than healthy age-matched controls [testosterone, 3.4 ± 0.5 vs. 5.6 ± 1.0 µg/liter (P = 0.0078); DHT, 0.55 ± 0.21 vs. 0.95 ± 0.29 nmol/liter (P = 0.046)], so the issue of the effect of hyperprolactinemia per se could not be completely evaluated. In any case, it is very likely that in the human model of prolactinoma, testosterone and DHT levels lower than normal or in the low normal range have the major effect on prostate size. To further investigate this, men with prolactinomas receiving replacement testosterone therapy, but with still high PRL levels, should be investigated; these patients with resistant prolactinomas were not enrolled in this pilot study.
In conclusion, in young men with PRL-secreting adenomas, PRL excess is unlikely to have effects on the prostate per se, because it is accompanied by low testosterone levels that produce the major effects. In accordance with previous findings (19), the lower IGF-I and IGFBP-3 levels may also play an additive effect in reducing prostate size. An increase in prostate size was observed after treatment with cabergoline together with an increase in testosterone and DHT until normal levels were reached. Thus, a direct relevant role of PRL in inducing prostate hypertrophy in men does not seem to be very likely, although at present no data are available in the few patients with resistant prolactinomas who require testosterone replacement.
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Footnotes |
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Abbreviations: DHT, Dihydrotestosterone; IGFBP-3, IGF-binding protein-3; PRL, prolactin; PSA, prostate-specific antigen; PV, prostate volume; TRUS, transrectal ultrasonography.
Received November 30, 2003.
Accepted March 10, 2004.
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