oxytocin and Prostatic-Hyperplasia

Benign prostatic hyperplasia (BPH) is a leading disorder of the elderly male population that is characterised by a progressive enlargement of prostatic tissue, resulting in obstruction of the proximal urethra and causing urinary flow disturbances. The pathophysiology of BPH associated with lower urinary tract symptoms is characterised by increased adrenergic tone (dynamic component) leading to smooth muscle contraction and prostatic overgrowth due to androgenic stimulation (static component); therefore, the therapeutic armamentarium of BPH can be broadly divided into antiadrenergic and antiandrogenic approaches. alpha1-Adrenoceptor antagonists and 5alpha-reductase inhibitors are well-established representatives of the two categories, respectively. Other antiandrogenic approaches involve gonadotropin-releasing hormone agonists and antagonists for the treatment of prostate hyperplasia. Apart from these approaches, new approaches with novel targets are emerging. The advent of new therapies is, however, more oriented towards the static component. These involve metabolic factors (hexokinase inhibitor), growth factors (vitamin D3 analogues), oxytocin antagonists and gonadotropin-releasing hormone Gi agonist-based therapies. Gene therapy and photodynamic therapies are other emerging therapies for relieving symptoms in BPH patients. With the initial success of upcoming targets, the unmet need to develop an efficacious and relatively safe therapeutic modality is discussed. Nevertheless, their long-term safety and efficacy needs to be evaluated in large-scale clinical trials. The future also belongs to combination therapies to combat both dynamic and static disease components and for extended indications such as micturition disorder and non-bacterial prostatitis.

Topics: Adrenergic alpha-Antagonists; Androgen Antagonists; Androgen Receptor Antagonists; Cholestenone 5 alpha-Reductase; Drug Therapy, Combination; Genetic Therapy; Gonadotropin-Releasing Hormone; Hexokinase; Humans; Male; Oxytocin; Photochemotherapy; Prostatic Hyperplasia

It is now well established that the peptide oxytocin can act as a paracrine factor as well as a classic hormone. Oxytocin is produced locally in both the testis and ovary, where it may modulate both steroidogenesis and contractility of the male and female reproductive tracts. The peptide is also present in the prostate and seminal fluid and there is growing evidence that oxytocin may be produced in the prostate. Within the prostate, oxytocin has been shown to increase growth of the epithelial tissue and increase both muscular tone and contractile activity. Furthermore, prostatic concentrations of the peptide are regulated by androgens. It is hypothesized that oxytocin may act as a paracrine factor to regulate cell growth and that this may be secondary to its effects on the enzyme 5 alpha-reductase which converts testosterone to dihydrotestosterone. In addition, oxytocin may be involved in the pathophysiology of benign prostatic hyperplasia.

Topics: Humans; Male; Oxytocin; Paracrine Communication; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

It is now well established that oxytocin is present in the mammalian testis and there is growing evidence that the peptide plays a role in the male reproductive tract by both assisting sperm transport and modulating steroidogenesis. In the testis, oxytocin has been shown not only to modulate testosterone production but also to increase the activity of the enzyme 5 alpha-reductase which converts testosterone to dihydrotestosterone (DHT). The prostate is an androgen-dependent organ with DHT being the active steroid. Oxytocin is present in the mammalian prostate. We have shown in the rat that levels of the peptide can be regulated by androgens, prostatic oxytocin concentrations being decreased by testosterone and increased following castration or treatment with an antiandrogen. Oxytocin treatment increases 5 alpha-reductase activity in the prostate of healthy young rats but, unlike the testis, this rise in enzyme activity is only transient. We thus propose that a local feedback mechanism may act to control prostatic levels of DHT and hence prostatic growth. Benign prostatic hyperplasia (BPH) is a common disease which affects both men and dogs. The aetiology of the disease is complex but both DHT and aging are important factors. Oxytocin levels are raised in prostatic tissue from dogs with BPH and the increase in peptide is accompanied by increased 5 alpha-reductase activity. Preliminary findings also suggest that prostatic oxytocin levels are raised in tissue from men with BPH. These data lead us to suggest that oxytocin may be involved in the pathophysiology of the prostate gland.

Topics: Aging; Animals; Dihydrotestosterone; Dogs; Humans; Male; Oxytocin; Prostate; Prostatic Hyperplasia; Rats; Testis

Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R

Topics: Aged; Cell Proliferation; Humans; Male; Middle Aged; Muscle Contraction; Muscle Tonus; Muscle, Smooth; Oxytocin; Prostate; Prostatic Hyperplasia; Receptors, Oxytocin; Vasotocin

Androgen-binding protein (ABP) and oxytocin (OT) are among the factors that control smooth muscle proliferation and tumour growth through oxytocin receptor (OTR). A close functional interaction of OTR and caveolin 1 has been shown to modulate cell growth and proliferation. We investigated samples from 10 patients (mean age 68.3) who underwent transurethral prostate resection because of benign prostate hyperplasia (BPH) by immunohistochemistry. Post-mortem prostate samples of three young men (age 18, 28, 33) were used as controls. Tissue samples were embedded in epoxy resin and cut into serial 1 microm sections for colocalization of ABP, OTR, proliferation marker p21 and caveolin 1. ABP was found in stroma of the smooth muscle cells in all studied samples. OTR staining occurred in most of these cells in BPH while controls contained only scattered cells positive for OTR. There were no apparent differences in immunostaining for p21 while immunoreactivity for caveolin 1 was observed in most cells in BPH and only in few cells in controls. Caveolin 1 was mostly colocalized with ABP and OTR in BPH samples while controls did only occasionally show this colocalization. Our observations indicate an interaction of ABP and OTR, associated with caveolin 1, which may account in part for known non-genomic actions of gonadal steroids. Androgen dependent prostate growth in BPH may be linked to these mechanisms.

Topics: Adult; Aged; Androgen-Binding Protein; Case-Control Studies; Caveolin 1; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Humans; Immunohistochemistry; Male; Oxytocin; Prostate; Prostatic Hyperplasia; Receptors, Oxytocin; Tissue Distribution

Oxytocin (OT) is implicated in regulating prostate growth. OT concentrations are increased in benign, and decreased in malignant prostate disease. This study investigated whether the altered concentrations of OT present in prostate disease affect the proliferation of malignant and non-malignant human prostate cells.. The effects of varying concentrations of OT and gonadal steroids on cell proliferation of non-malignant prostatic epithelial (PrEC) and stromal (PrSC) cells and androgen dependent (LNCaP) and independent (PC-3) malignant cell lines were assessed.. OT (>0.5 nmol . L(-1)) had no effect on PrEC proliferation when cells were cultured alone. When co-cultured with PrSC and gonadal steroids, OT inhibited epithelial cell proliferation. OT inhibited PrSC proliferation, when cells were cultured alone. When PrSC were co-cultured in the presence of estrogen physiological concentrations of OT were inhibitory. No effect on cell proliferation was observed with higher concentrations of OT. OT did not affect the proliferation of malignant cell lines in the absence of androgens but, in the presence of testosterone, low concentrations of OT (<1 nmol . L(-1)) stimulated proliferation of PC-3 cells. Disruption of caveolae in the plasma membrane removed the inhibitory effect of OT on PrSC proliferation but did not affect the stimulatory effect of OT on PC-3 cells cultured in the presence of androgens.. Changes in prostatic concentrations of OT that occur with aging and malignant disease may act to facilitate cell proliferation. The localization of the OT receptor within the plasma membrane modulates OT's proliferative response in the prostate.

Topics: Aging; Androgens; Caveolae; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Epithelial Cells; Humans; Male; Oxytocin; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Oxytocin; Testosterone

Oxytocin (OT) concentrations are elevated in prostate tissue of patients with benign prostatic hyperplasia (BPH). Oxytocin specifically increases growth, 5 alpha-reductase activity and contractility in the prostate. In the rat prostatic OT concentrations are regulated by gonadal steroids, with androgens reducing but oestrogens increasing OT concentrations. The regulation of prostatic oxytocin in man is not understood. This study investigates the effects of gonadal steroids on oxytocin production by the human prostate. Primary explants (approx. 1 mm3) of prostate tissue from patients with BPH were incubated in Dulbecco's modified Eagle's media in the absence or presence of 10 nmol/L testosterone (T), 10 nmol/L dihydrotestosterone (DHT), T or DHT plus 100 nmol/L of the anti-androgen cyproterone acetate (CPA), 55 pmol/L diethylstilbestrol (DES), or DES plus DHT. The amount of oxytocin secreted into the media after 3 days was measured by radioimmunoassay. Testosterone and DHT significantly increased oxytocin concentrations secreted into the media from 0.86 +/- 0.11 ng/g of tissue (control) to 1.51 +/- 0.14 ng/g (p < 0.01) and 1.54 +/- 0.13 ng/g (p < 0.05), respectively. Incubation of tissue samples with CPA resulted in oxytocin concentrations similar to control levels. Treatment with DES caused a significant increase from 1.99 +/- 0.71 to 3.98 +/- 1.36 ng/g (p < 0.05). A similar increase was measured in media of tissue incubated in DES plus DHT (p < 0.001). The results demonstrate that, unlike the rat where androgens decrease oxytocin, in hyperplastic human prostate tissue both androgens and oestrogens increase oxytocin. This imbalance in the regulation of oxytocin may result in promoting prostatic overgrowth in the pathogenesis of BPH.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Androgens; Animals; Cyproterone Acetate; Diethylstilbestrol; Dihydrotestosterone; Humans; In Vitro Techniques; Male; Middle Aged; Oxytocin; Prostate; Prostatic Hyperplasia; Radioimmunoassay; Rats; Testosterone; Time Factors

In this work, we showed the presence of atrial natriuretic factor (ANF) in human prostate and compared its localisation in normal and hyperplastic conditions. ANF was localised in epithelial and stromal cells, being increased in hyperplasia, mainly in the stromal component. Moreover, we compared ANF and oxytocin positivity in the same glands, focusing on the possible relationship between the paracrine effects of these two hormones.

Topics: Atrial Natriuretic Factor; Humans; Immunoenzyme Techniques; Male; Oxytocin; Prostate; Prostatic Diseases; Prostatic Hyperplasia; Stromal Cells