Correlation of NM23-H1 cytoplasmic expression with metastatic stage in human prostate cancer tissue.

Nm23-H1 has been identified as a metastatic suppressor gene in murine melanoma cell lines. Several functions have been attributed to its activity in cancer, including a histidine kinase activity, DNA repair, and regulation of other proteins involved in metastatic formation. While in breast cancer, NM23-H1 overexpression indicates a benign status through impairing progression of disease, its function is opposite in other cancers; e.g., neuroblastoma. To further understand this dichotomy of function in cancer, we have analyzed its function in prostate cancer, in which the relationship between NM23-H1 expression and prognostic state is today controversial. In vitro, overexpression of NM23-H1 in PC3 cells inhibited their cell motility, while downregulation of NM23-H1 expression in these cells by RNA interference showed enhanced cell motility. Immunohistochemistry analysis performed on 346 prostate cancer tissue samples showed a relationship between high levels of NM23-H1 expression in the nuclei of these tumorigenic cells and elevated Gleason score, with high levels of NM23-H1 cytoplasmic staining related to metastatic stage. This retrospective survival study demonstrates that high levels of NM23-H1 expression in the cytoplasm determine recurrence of prostate-specific antigen levels only in those patients with metastatic disease. Our findings suggest a correlation between high levels of NM23-H1 protein in the cytoplasm of the cells and progression of prostate cancer to metastasis, thus definitively identifying NM23-H1 as a new negative prognostic marker in prostate cancer.

The treatment with cabergoline for 24 month normalizes the quality of seminal fluid in hyperprolactinaemic males.

BACKGROUND: Alterations of sperm number and motility are found in hyperprolactinaemic men. Cabergoline treatment reverses alterations in semen. No information is currently available on the quality of seminal tests in hyperprolactinemia in response to cabergoline treatment. OBJECTIVE: To further investigate the effect of hyperprolactinaemia and its treatment with cabergoline on semen quality. PATIENTS: Forty-three men with hyperprolactinaemia (32 macro- and 11 micro-prolactinomas); 60 healthy men served as control. METHODS: Live spermatozoa count, sperm membrane function, kinetic index, nuclear DNA integrity, sperm curvilinear and linear velocity and amplitude of lateral movement of the sperm head were investigated before and after 6 and 24 months of treatment with cabergoline. STUDY DESIGN: Open prospective. RESULTS: At study entry, semen functional tests were severely and similarly impaired both in patients with macro- and micro-prolactinomas compared to controls. After 6 and 12 months of treatment there was a significant improvement of semen quality in patients achieving normalization of prolactin levels, although most of the parameters remained lower than in controls. After 24 months of treatment, seminal fluid characteristics were similar to the controls except for live spermatozoa count, sperm membrane function, sperm kinetic index and sperm nuclear DNA integrity, which remained abnormal in 9.3-53% of the patients. CONCLUSIONS: Twenty-four months of cabergoline treatment restored gonadal function in 66.7% of men with hyperprolactinaemia.

Correlation between seminal carnitine and functional spermatozoal characteristics in men with semen dysfunction of various origins.

BACKGROUND AND OBJECTIVE: L-carnitine is an essential molecule involved in mitochondrial metabolism, controlling the transport of acetyl and acyl groups across the mitochondrial inner membrane. Carnitine and acetylated carnitine (L-acetylcarnitine) are found in high concentrations in the epididymis, where they also act as antioxidants, protecting spermatozoa against damage caused by reactive oxygen species. In this open study we investigated the correlation between seminal carnitine levels and spermatozoal function, and the effect of combined L-carnitine + L-acetylcarnitine therapy, in infertile men. PATIENTS AND METHODS: 170 infertile men were enrolled in this study. Patients were divided into those with a total sperm motility below the normal WHO range (<50% motility, group 1 [n = 102]) and those with total sperm motility within the normal range (> or =50% motility, group 2 [n = 68]). Patients in group 1 were further divided into two groups: those with primary or secondary azoospermia (1B [n = 36]), and those without (1A [n = 66]). Patients in group 1A received L-carnitine 1 g/day and L-acetylcarnitine 500 mg twice daily for 6 months. Seminal carnitine levels were measured and correlated with sperm count and motility, eosin test, hypo-osmotic swelling test, acridine orange test for sperm nuclear DNA integrity and sperm kinetics evaluated by computer-assisted sperm analysis in all patients. RESULTS: There was a significant correlation between seminal carnitine concentration and sperm concentration, total sperm count, sperm total motility, rapid forward progression, live sperm count, membrane function, nuclear DNA integrity, capacity for cervical mucus penetration, linearity of spermatic movement, and amplitude of lateral sperm head movement (all p < 0.0001) in the entire study population. In group 1A, there was a significant increase in total motility, live sperm count, membrane integrity and linearity of spermatic movement after 3 and 6 months of L-carnitine/L-acetylcarnitine treatment, and in capacity for cervical mucus penetration after 6 months of treatment, compared with baseline. CONCLUSION: Seminal carnitine concentration may be an appropriate marker of sperm and epididymal function. L-carnitine/L-acetylcarnitine treatment may be an effective therapy to improve mainly functional seminal parameters.

PRL secreting adenomas in male patients.

Prolactinomas are the most frequent pituitary tumors and their frequency varies with age and sex, occurring most frequently in females between 20-50 yr-old. In men, hyperprolactinaemia is often present for many years without symptoms, as generally the most important symptoms are the decrease in libido and/or sexual potency both underestimated by the majority of the patients. Prolactin (PRL) plays a role in the process of spermatogenesis, and normal serum PRL levels are required for normal testicular function. On the other hand, hyperprolactinaemia has multiple negative effects on the gonadal axis. As a consequences hyperprolactinemic males show alteration of sexual potency and seminal fluid quality. Cabergoline treatments is able to induce normalization of PRL levels and a reduction of tumor mass in the majority of patients and consequently restoring the normal semen quality and ameliorating the quality of life of men with pituitary PRL-secreting adenoma.

Outcome of cabergoline treatment in men with prolactinoma: effects of a 24-month treatment on prolactin levels, tumor mass, recovery of pituitary function, and semen analysis.

The outcome of 24 months of cabergoline treatment on prolactin (PRL) normalization, tumor shrinkage, restoration of pituitary function, and semen alterations was prospectively investigated in 41 men with macro- (age 17-70 yr) and 10 with microprolactinoma (age 18-53 yr). Fifty-one age-matched men served as controls for semen analysis. At study entry, of the 41 patients with macroprolactinoma, 17 (41.4%) had visual field defects, 14 (34.1%) had headache, eight (19.5%) had galactorrhea, 22 (53.6%) had hypopituitarism apart from hypogonadism, and 30 (73.2%) had low testosterone levels; of the 10 patients with microprolactinoma, none had visual field defects, galactorrhea, or hypopituitarism apart from hypogonadism, two had headache (20%), and five had low testosterone levels (50%; P = 0.3). After 24 months of therapy, 1) PRL levels normalized in 31 patients with macro- (75.6%) and in eight with microprolactinoma (80%; P = 0.9), and galactorrhea disappeared in all patients; 2) maximal tumor diameter reduced by 73.7 +/- 22.6% in macro- and 72.8 +/- 28.3% in microprolactinomas (P = 0.91), and 15 macro- (30%) and seven microprolactinomas (46.7%; P = 0.37) disappeared; 3) visual field defects disappeared in 15 (75%) patients with macroprolactinoma, and headache disappeared in 15 (83%) patients with macro- and in one with microprolactinoma (50%); 4) GH secretion recovered in 62.5% and ACTH secretion in 60% of patients; 5) testosterone levels normalized in 25 patients with macro- (60.9%) and six with microprolactinoma (60%) after 6 months, and 20 patients required testosterone or gonadotropin replacement (in 14 or six patients, respectively); and 6) sperm volume and count normalized in all patients who normalized testosterone levels, whereas motility normalized in more than 80%. Cabergoline therapy was well tolerated; only 4.5% of patients had side effects at high doses. These data demonstrate that cabergoline treatment is as effective and safe in men as in women with prolactinoma and can be successfully used as primary therapy even in men bearing large macroprolactinomas.

Six months of treatment with cabergoline restores sexual potency in hyperprolactinemic males: an open longitudinal study monitoring nocturnal penile tumescence.

This open longitudinal study investigated the prevalence of depressed sexual potency by monitoring erectile dysfunction using nocturnal penile tumescence (NPT) in 51 consecutive men with hyperprolactinemia (41 macroprolactinomas and 10 microprolactinomas) and evaluated potential reversibility of sexual failure after 6 months of treatment with cabergoline. Fifty-one healthy men served as controls. Compared with controls, the patients with either micro- or macroprolactinoma had low testosterone levels with severe alterations of erectile function. Testosterone deficiency was present in 73.2% of macro- and 50% of microprolactinomas; reduced libido and sexual potency were referred by 53.6% of macroprolactinomas, 50% of microprolactinomas, and none of controls. Fewer than three erectile events per night by NPT were found in 96.7% of patients and 13.7% of controls (P < 0.0001). After 6 months of cabergoline treatment, prolactin levels normalized in 74.5% of patients: 73.2% of macroprolactinomas and 80% of microprolactinomas. Testosterone levels normalized in 68.6% of patients, whereas NPT normalized in 60.6% of patients who had normalized prolactin levels and in 7.7% of patients who did not. In conclusion, at study entry, 50% of the patients complained of sexual disturbances, 96.7% of whom had an impairment of erectile events per night compared with 13.7% of controls. Six months of treatment with cabergoline normalized testosterone levels in most cases, thus restoring and maintaining during treatment the capability of normal sexual activity in hyperprolactinemic males.

Traffic pollutants affect fertility in men.

BACKGROUND: Given the lack of consensus about the effect of traffic-derived pollutants on male fertility, we evaluated semen quality in men occupationally exposed to traffic. METHODS: Semen quality was investigated in 85 men employed at motorway tollgates and in 85 age-matched men living in the same area. Semen, circulating sex hormones, methaemoglobin, sulphaemoglobin, carboxyhaemoglobin, lead (Pb) and zinc (Zn) protoporphyrin were assayed. Environmental carbonium oxide, nitrogen oxide, sulphur oxide and Pb were also measured. RESULTS: Sperm count, and serum levels of FSH, LH and testosterone were within normal range in both groups. Total motility, forward progression, functional tests and sperm kinetics were significantly lower in tollgate workers versus controls. In a subset of tollgate workers with motility below normal, methaemoglobin was inversely correlated with total motility, viability, the hypo-osmotic swelling test, the acridine orange test, the cervical mucus penetration test, linearity, and amplitude of lateral movement of the sperm head, whereas blood levels of Pb were inversely correlated with viability and sperm count. CONCLUSIONS: The finding that blood methaemoglobin and Pb were inversely correlated with sperm parameters indicates that nitrogen oxide and Pb adversely affect semen quality.

Hyperprolactinemia in men: clinical and biochemical features and response to treatment.

Hyperprolactinemia induces hypogonadism by inhibiting gonadotropin-releasing hormone pulsatile secretion and, consequently, follicle-stimulating hormone, luteinizing hormone, and testosterone pulsatility. This leads to spermatogenic arrest, impaired motility, and sperm quality and results in morphologic alterations of the testes similar to those observed in prepubertal testes. Men with hyperprolactinemia present more frequently with a macroadenoma than a microadenoma. Symptoms directly related to hypogonadism are prevalent. In men hypogonadism leads to impaired libido, erectile dysfunction, diminished ejaculate volume, and oligospermia. It is present in 16% of patients with erectile dysfunction and in approx 11% of men with oligospermia. Treatment with bromocriptine or cabergoline (CAB) is effective in men with prolactinomas, with a response that is in general comparable to treatment in women. Seminal fluid abnormalities rapidly improve with CAB treatment, while other dopaminergic compounds require longer periods of treatment. Moreover, to improve gonadal function in men, the integrity of the hypothalamic-pituitary-gonadal axis is necessary. New promising data indicate that a substantial proportion of patients with either micro- or macroprolactinoma do not present hyperprolactinemia after long-term withdrawal from CAB. Whether this corresponds to a definitive cure is still unknown, but treatment withdrawal should be attempted in patients achieving normalization of prolactin levels and disappearance of tumor mass to investigate this issue.