AKT and AMPK activation after high-fat and high-glucose in vitro treatment of prostate epithelial cells.

Considering the increasing consumption of saturated fat and glucose in diets worldwide and its possible association to carcinogenesis, this investigation analysed the proliferation profile of nonmalignant human prostate epithelial cells after exposure to elevated levels of fat and glucose. PNT1A cells were cultured with palmitate (100 or 200 µM) and/or glucose (450 mg/dl) for 24 or 48 h. Treated cells were evaluated for viability test and cell proliferation (MTS assay). AKT and AMPK phosphorylation status were analysed by Western blotting. After 24 h of high-fat alone or associated with high-glucose treatment, there was an increase in AMPK and AKT activation associated to unchanged MTS-cell proliferation. Following 48 h of high-fat but not high-glucose alone, cells decreased AMPK activation and maintained elevated AKT levels. These data were associated to increased cell proliferation after further high-fat treatment. After longer high-fat exposure, MTS revealed that cells remained proliferating. High-glucose alone or associated to high-fat treatment was not able to increase cell proliferation and AKT activation. A high-fat medium containing 100 µM of palmitate stimulates proliferation in PNT1A cells by decreasing the activation of AMPK and increasing activation of AKT after longer exposure time. These findings improve the knowledge about the negative effect of high levels of this saturated fatty acid on proliferative disorders of prostate.

New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists.

Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability.

Clinical trial update and novel therapeutic approaches for metastatic prostate cancer.

Recurrent prostate cancer (PCa) remains a major clinical challenge. Invasive and metastatic PCa lesions often exhibit a partial and time-limited response to therapy before the cancer progresses and the patient succumbs to the disease. Despite recent advances in early diagnosis and treatment, approximately one-third of treated patients will relapse and become resistant to currently available treatments. In this review we evaluate current treatment practices and recent advances in therapy for localized prostate malignancy and advanced, metastatic prostate cancer. Some of the promising new drugs for PCa treatment include MDV3100, an androgen receptor (AR) antagonist that prevents androgens from binding to the AR and nuclear translocation and co-activator recruitment of the ligand-receptor complex; abiraterone, an orally administered drug that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17; and several newer cytotoxic drugs (epothilones, satraplatin). Key new insights are that cancer stem cells play a role in PCa and that PCa cells are dependent on the AR for proliferation, even in the hormone refractory state of the disease. We also discuss potential molecular targets for new drug candidates for the treatment of metastatic PCa.

Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel.

Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

Octreotide scintigraphy and Chromogranin A do not predict clinical response in patients with octreotide acetate-treated hormone-refractory prostate cancer.

In this pilot study, the predictive value of Octreotide scintigraphy (Octreoscan) and/or Chromogranin-A (CgA) was investigated in patients with hormone-refractory prostate cancer treated with Octreotide acetate. In total, 20 patients with progressive disease and bone metastases entered the trial. At baseline Octreoscan, CgA, PSA, alkaline phosphates (ALP) and two self-administered questionnaires (EORTC QLQ C-30 (v3) and brief pain index) were performed and a diary of the pharmaceutical was started. The treatment consisted of Octreotide (Sandostatin LAR) acetate 30 mg intramuscular injection every month. The blood samples and questionnaires were repeated every month until 3 months. Clinical responder was defined as a patient with increased global health score more than 10 units and stable or decreased pain score without an increase in analgesic. In all, 17 patients were treated per protocol, and four were assessed as clinical responders. Six patients developed a reduction in ALP (median -26%, range -5 to -78%). All patients increased in PSA. At baseline, three patients had a negative Octreoscan and the patients with positive lesions, demonstrated uptake of low intensity. At baseline the CgA was elevated above the normal range in 15 of the patients, and during treatment five patients decreased their CgA to the normal range. Neither baseline Octreoscan nor CgA could identify the clinical reponders. A minority of patients improves their health-related quality of life. The decrease and normalization of CgA levels in five patients during therapy indicates therapeutic activity but Octreoscan and CgA could not identify clinical responders.

Risks and benefits of hormonal manipulation as monotherapy or adjuvant treatment in localised prostate cancer.

A round table meeting was held to discuss the role of hormonal therapy in localised prostate cancer. The findings of the group were that immediate hormonal therapy does not provide an overall survival advantage in localised and locally advanced prostate cancer. Bicalutamide can prolong disease free survival in patients with locally advanced prostate cancer, however it is important to underline that at this time it has not been shown to influence disease specific nor overall survival. It remains also unproven that early treatment is superior to treatment at progression. However, a trend towards decreased survival with bicalutamide was observed in low risk patients such as those with localised disease. In patients receiving bicalutamide, there were increased cardiovascular side-effects, in addition to the high incidence of gynaecomastia. Early hormonal therapy has to be balanced against such side-effects and the inevitable appearance of hormone refractory disease in patients who progress after hormonal therapy. Consequently, patients with localised, low risk disease are not considered appropriate candidates for hormonal therapy used either as mono-therapy or in the adjuvant setting.

Expression of serotonin receptors 2B and 4 in human prostate cancer tissue and effects of their antagonists on prostate cancer cell lines.

OBJECTIVES: Overexpression of receptors to neuroendocrine (NE) cell products has been suggested to contribute to development of hormone-refractory prostate cancer (HRPC). In this study, we evaluated the expression of 5-HTR2B and 5-HTR4 in HRPC, and the effects of their antagonist on PC cell line growth. METHODS: Proteins and mRNA expression was determined by immunohistochemistry, western blot and RT-PCR. Growth inhibition of PC cell lines was determined in vitro using ELISA-BrdU proliferation assay and cell cycle was evaluated by flow cytometry. RESULTS: Immunostaining of 5-HTR2B was observed in low-grade and high-grade tumours, PIN and BPH cells, and in vascular endothelial cells, whereas 5-HTR4 was found predominantly in high-grade tumours. This result was confirmed by western blot analysis. At the mRNA level, 5-HTR4 mRNA was expressed in DU145 and LNCaP cells. Antagonists to both receptor subtypes inhibited proliferation of PC cells in a dose-dependent manner. CONCLUSIONS: The present result indicate that 5-HTRs are present at various tumour stages and that antagonists to these receptors can inhibit the proliferative activity of androgen-independent PC cell lines.

Long-term testosterone stimulation induces hyperplasia in the guinea-pig prostate.

The relation between supraphysiologic circulating testosterone levels and prostatic diseases is unclear and difficult to study in men. Animal models may be advantageous. Based on a pilot study, testosterone enantate 50 mg (n=12) or 25 mg (n=12) was administered to guinea-pigs intramuscularly every 3 weeks, for either 7 or 14 months. The histopathology of the prostate was described. Epithelial hyperplasia was found in 14/21 animals receiving testosterone and in 7/12 very old animals, but no such changes were found in the sham or castrated animals. Testosterone stimulation seems to induce epithelial hyperplasia, but not cancer, in the guinea-pig prostate.

Expression of serotonin receptors and role of serotonin in human prostate cancer tissue and cell lines.

BACKGROUND: Increase in the number of serotonin (5-HT) releasing neuroendocrine (NE) cells has been shown to be correlated with tumor progression, loss of androgen dependence, and poor prognosis. Serotonin is a well-known mitogen which mediates a wide variety of physiological effects via multiple receptors, of which receptor subtype 1 (5-HTR1) has been identified in prostate cancer (PC) cell lines. Recently, 5-HT has been found to show growth-promoting activity and to be functionally related to oncogenes. MATERIALS AND METHODS: Localization, protein content, and mRNA expression of 5-HTR subtype 1A, 1B, and 1D was studied in prostatic tissue (35 patients), metastases, PC cell lines, a benign prostatic stromal cell line (human prostate cell preparation (hPCP)), and xenografts of PC-3 cells by immunohistochemistry (IHC), Western blotting, and RT-PCR, respectively. The growth-inhibition effect of a 5-HT1A antagonist (NAN-190) on PC cell lines was studied using a bromodeoxyuridine (BrdU) assay. RESULTS: A strong immunoreaction of 5-HTR1A and 1B was demonstrated in high-grade tumor cells (35/35) and a small number of BPH cells, whereas 5-HTR1D was confined to vascular endothelial cells. 5-HTR1A was also demonstrated in PC cells metastasized to lymph node and bone, PC-3, DU145, LNCaP, and in xenografts of PC-3 cells and hPCP. Western blot analysis gave strong bands from PC tissue extracts compared to BPH tissue. Using RT-PCR, 5-HTR1A mRNA was demonstrated in all PC cell lines. An antagonist of 5-HTR1A (NAN-190) inhibited the growth of PC-3, DU145, and LNCaP cells but not of hPCP cells. CONCLUSIONS: This is the first study demonstrating an overexpression of 5-HTR subtypes 1A and 1B in PC cells, especially in high-grade tumors. Moreover, 5-HT stimulates proliferation of PC cells and 5-HTR1A antagonists inhibit proliferation. Thus, we propose that 5-HT has an important role in tumor progression, especially in the androgen-independent state of the disease. The design of specific antagonists for this type of receptor might be useful for the growth control of androgen-independent tumors.

No association between mutations in the human androgen receptor GGN repeat and inter-sex conditions.

The functional role of the GGN repeat in the human androgen receptor gene is unknown, although mutations in this region have been found in patients with inter-sex conditions. We have investigated the prevalence of GGN mutations in the androgen receptor in the Swedish population and their relation to male reproductive function. A physical examination and semen analysis was carried out in 223 men under medical examination before military service and in 94 men referred due to infertility and having sperm concentrations <5 x 10(6)/ml. The GGN and CAG repeats in the androgen receptor gene were directly sequenced. Both populations contained two predominant alleles of 23 and 24 GGN repeats, 83.8 and 90.5% respectively. Four mutations, three in the conscripts and one among the infertile men, were found, resulting in three GGC to GGT substitutions and one GGT to GGC substitution. None of the men presented with genital abnormalities, but two conscripts had low ejaculate volumes (0.3 and 0.9 ml). All men carrying a mutation also had GGN lengths >or=24. Three subjects with GGN >24, with no mutations and with normal seminal volumes, were also found. Our findings indicate that point mutations in the GGN repeat are frequently found in the general male population (1.3%; 95% CI: 0.3-3.9%), but are usually not associated with profound changes in the male phenotype.

Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial.

OBJECTIVE: To describe the outcome, assessed as the level of prostate specific antigen (PSA), of a mature (more than half the events recorded) prospective randomized study with a median follow-up of 82 months of neoadjuvant hormonal therapy before radical prostatectomy, as this has been suggested to decrease the rate of positive surgical margins (i.e. provide greater potential to completely excise the tumour). PATIENTS AND METHODS: From December 1991 to March 1994, 126 patients with clinically localized prostate cancer were randomized between direct radical prostatectomy or a 3-month course of a gonadotrophin-releasing hormone analogue before surgery. The patients were followed by PSA determinations and a value of > 0.5 ng/mL used to define progression. RESULTS: The incidence of positive surgical margins decreased from 45.5% to 23.6% (P = 0.016) with hormone treatment. Despite this there was no difference in PSA progression-free survival at the last follow-up; it was 51.5% for those undergoing radical prostatectomy only and 49.8% for those who received hormonal pretreatment (P = 0.588). CONCLUSIONS: Three months of neoadjuvant hormonal therapy before radical prostatectomy offers no benefit to the patient and cannot be recommended for routine clinical use.

Determination of serum prostate-specific antigen-alpha1-antichymotrypsin complex for diagnosis of prostate cancer in Japanese cases.

OBJECTIVE: The clinical utility of the determination of serum prostate-specific antigen-alpha1-antichymotrypsin complex (PSA-ACT) for the diagnosis of prostate cancer, especially in cases in the diagnostic gray zone, is still unclear. MATERIAL AND METHODS: With the use of a newly approved enzyme immunoassay for the detection of PSA-ACT, 907 sera, including those from non-urological benign and malignant diseases, were analysed. RESULTS: Serum values of PSA-ACT in non-prostate cancer males increased according to age from the 40s to 70s. The serum values were high only in the patients with prostatic diseases and, in prostate cancer patients, the values became high as the clinical stage progressed. By receiver-operating characteristic analysis significantly better results in PSA-ACT than total PSA were observed. In the group with a total PSA of 2-20 ng/ml, the detection of PSA-ACT showed better results, although not significantly so, than the free-to-total PSA ratio. CONCLUSIONS: The detection of PSA-ACT showed a high clinical utility in the diagnosis of prostate cancer. Therefore, it may replace total PSA determination.

Semiquantitative morphology of human prostatic development and regional distribution of prostatic neuroendocrine cells.

BACKGROUND: The neuroendocrine cells of the human prostate have been related to proliferative disorders such as prostatic cancer. Their origin, distribution, and development have therefore been studied and discussed in terms of current stem cell concepts in the prostate. METHODS: Prostatic tissue specimens (n = 20) from human fetuses (n = 8), prepubertal and pubertal children (n = 8) and mature men (n = 4) were studied immunohistochemically using antibodies directed against neuroendocrine, epithelial as well as secretory markers. Semiquantitative computer-assisted evaluation of different epithelial and stromal components based on stereological principles was performed on azan-stained sections representative of all developmental stages. RESULTS: By the end of gestational Week 9, neuroendocrine (NE) cells appear in the epithelium of the urogenital sinus and are subsequently closely associated with the formation of urethral prostatic buds. The fetal and postnatal distribution pattern of NE cells within the gland is characterized by a relatively constant number of cells per gland similar to prostatic smooth muscle cells. Likewise, a density gradient exists with the highest density in the large collicular ducts and almost no NE cells in subcapsular peripheral acini. In peripheral ducts, the distribution is random. Maturation of the NE cells precedes that of the secretory cells by about 10-16 years. CONCLUSIONS: A second prostatic stem cell lineage, different from the urogenital sinus (UGS)-lineage is hypothesized originating from immature neuroendocrine cells. Being morphologically indistinguishable from the UGS-derived prostatic secretory cell lineage, it gives rise to neuroendocrine cells. Their presence is apparently important for proliferation regulation of the UGS-derived lineage of the prostate.

Neuroendocrine cells and nerves in the prostate of the guinea pig: effects of peripheral denervation and castration.

BACKGROUND: Neuroendocrine (NE) cells and nerves in the prostate gland are thought to play a central role in the regulation of growth, cellular differentiation and homeostasis of secretory activity. The objective of this experimental study was to describe the effects of peripheral denervation and castration on NE cells and nerves in the guinea pig prostate. METHODS: Guinea pigs underwent sham-operation, unilateral and bilateral hypogastric nerve resection, extirpation of the right anterior major pelvic ganglion (AMPG), autotransplantation of prostatic tissue and castration. Cryostat sections of prostatic tissue were examined with immunohistochemistry by using serotonin (5-HT) and chromogranin A (CgA) and various neuropeptides. RESULTS: The number of 5-HT-IR NE cells was four-fold higher than CgA-IR NE cells. The innervation pattern was uniform throughout the gland with subepithelial nerves in close proximity to NE cells. Autotransplants of prostatic tissue showed total loss of nerves, but the number and morphology of 5-HT-IR NE cells were unaltered. Extirpation of the right AMPG showed significant reduction in prostate weight, decreased density of nerve terminals in the superior part of the ipsilateral prostate, whereas the number and morphological feature of 5-HT-IR NE cells remained unaffected in the entire prostate. Castration induced atrophy of the gland with a significant reduction in weight (unpaired t-test, P < 0.001), but without effect upon 5-HT-IR NE cells. CONCLUSIONS: The guinea pig seems to be a useful animal model for studies on the role of the NE cells in the prostate. NE cells seem to be independent of innervation and androgens. It seems that other factors influence the NE cell population to a greater extent.

Treatment of locally advanced prostate cancer--a new role for antiandrogen monotherapy?

Men with locally advanced prostate cancer face a high risk of disease progression and cancer-related death. The traditional active treatment options for locally advanced disease, either following failure of treatment of primary curative intent or newly diagnosed, are radiotherapy and castration. Radiotherapy alone has a high failure rate, although outcome can be improved by adjuvant hormonal therapy. Castration is associated with loss of libido, sexual dysfunction, osteoporosis and hot flushes, which are significant drawbacks when patients may receive treatment for several years. Monotherapy with a non-steroidal antiandrogen offers potential benefits with respect to quality of life. Studies in the adjuvant setting are in progress. In the setting of previously untreated locally advanced disease, pooled mature data (56% deaths) from two major studies indicate no significant difference in survival outcome between bicalutamide ('Casodex') 150 mg and castration. Bicalutamide 150 mg offers quality of life benefits with respect to sexual interest and physical capacity. Preliminary data suggest that bicalutamide maintains bone mineral density. Bicalutamide 150 mg is well tolerated; gynaecomastia and breast pain, common side effects of antiandrogen monotherapy, may be managed by prophylactic irradiation or surgery. Bicalutamide 150 mg monotherapy is an alternative to castration for locally advanced prostate cancer.

Neuroendocrine pathogenesis in adenocarcinoma of the prostate.

BACKGROUND: In the prostate, the importance of sex hormones for its normal development and function is well known. However, it has been proposed that various neuroendocrine (NE) hormones and growth factors may be involved in the pathogenesis of prostatic carcinoma (CaP). Neuroendocrine differentiation appears to be associated with tumour progression and the androgen-independent state, for which there is currently no successful therapy. Therefore, we need to improve our understanding of NE cells, their regulatory products and influence on the prostate gland. Finally, new therapeutic protocols need to be developed. METHODS: Information is presented on prostatic NE cells and neuroendocrine differentiation (NED) in prostatic carcinoma. Neuroendocrine secretory products and interactions with epithelial prostate cells are investigated in order to understand their significance for the pathogenesis of the prostate gland, prognosis and therapy. RESULTS: Recent research suggests that NE-secreted products. such as serotonin, somatostatin and bombesin, may influence growth, invasiveness, metastatic processes and angiogenesis in CaP. During recent years. new experimental models for NED have been developed to provide evidence that NE products may promote proliferation and confer antiapoptotic capabilities on non-neuroendocrine cells in close proximity to NE cells. Cancerous epithelial cells may become more responsive to NE factors by upregulation of receptors for neuropeptides, or may induce NE cells to upregulate the secretion and synthesis of NE factors. In the androgen independent state, neuropeptides and their intracellular signals may activate the androgen receptor. Furthermore, androgen ablation may lead to downregulation of neural endopeptidase 24.11 (a zinc-dependent metalloproteinase) and PSA, which would lead to increased levels of NE products becoming available. These studies confirm that NE cells and NED may have a significant impact on prostate cancer, especially in the androgen independent state. CONCLUSIONS: Recent developments in molecular biology and pathophysiology of prostate cancer have increased our understanding of the NE regulatory mechanisms. Hopefully, this will lead to the development of entirely new therapeutic modalities. For example, somatostatin agonists may suppress angiogenesis and proliferation, and simultaneously promote apoptosis in prostate cancer cells. Somatostatin may thus have an important role in tumour biology, and in the future there may be a potential role for somatostatin analogues in the treatment of prostate cancer, but also for serotonin and bombesin receptor antagonists. However, a review of the accumulated knowledge in this field suggests that we still need to improve our understanding of NE cells and their regulatory products and influence on the prostate gland. and that clinical trials are needed, to test drugs based on neuroendocrine hormones and their agonists/antagonists.

Palliative radiation with a radiolabeled diphosphonate (rhenium-186 etidronate) in patients with hormone-refractory disseminated prostate carcinoma.

MATERIAL AND METHODS: The present study investigates the safety and efficacy of 2590 MBq rhenium-186 (186Re) etidronate (i.e. twice the activity normally used) administered intravenously in 15 patients with disseminated prostatic carcinoma and bone pain. RESULTS: Pain relief was observed in 11 of 14 evaluable patients (79%), 4 of whom became completely free from pain. Five of the responding patients also noted an improvement in daily activity and two found it possible to reduce or discontinue morphine medication. Pain relief occurred within one week in four patients, and within two weeks in eight of the responding patients. The mean duration of pain relief after the first course of 186Re-etidronate was 6 weeks (range 4-10). The toxicity was mild (< or = grade 2), transient, and restricted to hematological toxicity. CONCLUSIONS: 186Re-etidronate provided rapid pain-relief and had mild toxicity in most patients with disseminated hormone-refractory prostatic carcinoma, but doubling the activity did not markedly improve the efficacy.

Calcitonin and calcitonin gene-related peptide in the human prostate gland.

BACKGROUND: Calcitonin-related peptides have been found in the human prostate, and calcitonin (CT) and calcitonin gene-related peptide (CGRP) have been demonstrated in subpopulations of neuroendocrine (NE) cells. The purpose of this study was to determine the concentrations of CT and CGRP as well as the densities of NE cells in normal prostates, benign prostatic hyperplasia (BPH), and carcinoma of the prostate (CAP). METHODS: In 42 specimens of radical prostatectomy, the number of CT- and CGRP-immunoreactive NE cells in areas of normal and BPH tissue was determined, and compared with CAP tissue using immunocytochemistry. In addition, by radioimmunoassay (RIA), tissue levels of CT and CGRP were analyzed in extracts from areas of normal, BPH, and CAP tissue, as verified by adjacent histologic sections. RESULTS: A significant decrease in CT-immunoreactive NE cells was observed in hyperplastic nodules of BPH in comparison to normal tissue. These findings were in parallel with a significant reduction in tissue CT level in BPH compared to normal tissue. There was also a marked, but statistically nonsignificant, reduction in CT levels in CAP tissue. In contrast, levels of CGRP in BPH and CAP tissue did not show any significant differences compared to normal tissue. CONCLUSIONS: CT and CGRP are present in NE cells of the human prostate. Calcitonin levels are significantly reduced in BPH, in parallel with a decreased number of CT-immunoreactive NE cells, whereas no significant changes in tissue levels of CGRP were observed. The functional significance of these findings is discussed.