Combination therapy with antioxidants improves total motile sperm counts: A Preliminary Study.

PURPOSE: Optimal strategies to treat idiopathic male infertility have remained unclear. The aim of this study was to evaluate the effectiveness of combination antioxidant therapy with several vitamins and supplements on semen parameters. METHODS: Thirty-one men with oligozoospermia and/or asthenozoospermia evaluated by a Makler counting chamber were randomly assigned to two treatment groups: a combination of antioxidant supplements (L-carnitine, zinc, astaxanthin, coenzyme Q10, vitamin C, vitamin B12, and vitamin E) and a Chinese herbal medicine, hochu-ekki-to (HE). Serum endocrinological profiles and semen parameters, especially total motile sperm count, were compared between before and after 12 weeks of treatment in both groups. RESULTS: In the supplement group, endocrinological findings were not significantly improved. The semen parameters of semen volume, sperm concentration, and sperm motility were not statistically significantly improved, whereas total motile sperm count was significantly improved. In contrast, none of the endocrinological factors or semen findings were significantly improved by the Chinese herbal medicine although semen concentration, semen motility, and total motile sperm count showed a tendency to increase. CONCLUSION: Because combination antioxidant therapy could improve sperm motility significantly for patients with idiopathic oligoasthenozoospermia, our supplement could be one treatment option for idiopathic male infertility.

The Impact of Increased Bladder Blood Flow on Storage Symptoms after Holmium Laser Enucleation of the Prostate.

In order to investigate how holmium laser enucleation of the prostate (HoLEP) improves urinary storage symptoms, we assessed blood flow in the urinary bladder mucosa of patients with benign prostatic hyperplasia (BPH) before and after laser surgery. Seventy-four consecutive patients with BPH (median age 69 years, range; 53-88) underwent HoLEP at our institution and are included in this study. We prospectively assessed the International Prostate Symptom Score (IPSS), IPSS-QOL Score, the Overactive Bladder Symptom Score (OABSS), uroflowmetry, and blood flow in the urinary bladder, before and after surgery. Blood flow in the bladder mucosa was measured using the OMEGA FLOW (OMEGAWAVE, Tokyo, Japan) laser Doppler flowmeter. The median volume of the enucleated adenomas was 45.0 g (range: 25.0 to 83.2). The median IPSS improved significantly from 20 (range: 6-35) to 3 (0-22) (p < 0.001; Wilcoxon signed-rank test), as did the storage symptoms score, which decreased from 13 (2-20) to 3 (1-8) (p < 0.001). Median bladder blood flow increased at the trigone from 9.57 ± 0.83 ml/sec to 17.60 ± 1.08 ml/sec. Multiple regression analysis for the improved storage symptom score eliminated all explanatory variables except increased bladder perfusion. The data suggest that HoLEP improves blood flow in the bladder mucosa, which independently leads to the improvement of storage symptoms.

Impact of hyponatremia on survival of patients with metastatic renal cell carcinoma treated with molecular targeted therapy.

OBJECTIVES: Hyponatremia is reported to be associated with poor survival in localized renal cell carcinoma and metastatic renal cell carcinoma treated with immunotherapy. However, there are no reports on the relationship between hyponatremia and prognosis of metastatic renal cell carcinoma treated with molecular targeted therapy. We evaluated the prognostic significance of hyponatremia in metastatic renal cell carcinoma treated with molecular targeted therapy as first-line therapy. METHODS: We retrospectively analyzed a database comprising 87 patients treated from April 2008 to July 2011 with sorafenib or sunitinib as first-line therapy for metastatic renal cell carcinoma. Patients were divided into three groups according to serum sodium level: severe hyponatremia (≤134 mEq/L), mild hyponatremia (135-137 mEq/L) and normal natremia (≥138 mEq/L). RESULTS: Median cancer-specific survival time was 8.8 months in the patients with severe and mild hyponatremia, and 32.6 months in the patients with normal natremia (P < 0.001). Multivariate analysis showed severe and mild hyponatremia to be significantly associated with cancer-specific survival (hazard ratio 6.228; 95% confidence interval 2.161-17.947, P = 0.001; hazard ratio 3.374; 95% confidence interval 1.294-8.798, P = 0.013), respectively. Neutrophilia and high C-reactive protein level (C-reactive protein ≥1.0 mg/dL) were significant prognostic factors to predict inferior cancer-specific survival. In Harrell's concordance index calculation, hyponatremia could significantly improve the predictive accuracy for estimation of survival probability (P = 0.028). CONCLUSIONS: Hyponatremia (<138 mEq/L), neutrophilia and high C-reactive protein levels seem to represent significant predictive factors for cancer-specific survival in metastatic renal cell carcinoma patients treated with molecular targeted therapy as first line therapy. Furthermore, hyponatremia might be significantly associated with chronic inflammation and tumor aggressiveness.

One-month relative dose intensity of not less than 50% predicts favourable progression-free survival in sorafenib therapy for advanced renal cell carcinoma in Japanese patients.

BACKGROUND: Sorafenib is a multikinase inhibitor used as a second-line treatment for metastatic renal cell carcinoma (mRCC). However, it is very difficult to estimate sorafenib dosage because it is difficult to maintain stable administration and dosage intervals due to several side-effects. We examined the correlation between relative dose intensity (RDI) and clinical outcome of sorafenib therapy in a multi-institutional study. METHODS: A study population of 70 first-line therapy-refractory patients with pathologically confirmed RCC was eligible for this investigation. Clinical outcomes were evaluated according to clinicopathological features and RDI for 1 month (1M-RDI). RESULTS: There was significant difference in progression-free survival (PFS) time but not overall survival (OS) time when the 1M-RDI cut-off value was ≥ 50%. In 15 patients (21.4%) with 1M-RDI of <50%, median PFS time was 4.1 months (95% I collagen (95% CI): 2.0-6.2), whereas it was 10.5 months (95% CI: 7.6-13.4) in the patients with 1M-RDI of ⩾50% (P=0.022). Multivariate analysis showed 1M-RDI status to be significantly associated with PFS (HR: 3.838, 95% CI: 1.658-8.883, P=0.002) but not OS (P=0.328). CONCLUSION: Although this study was retrospective, a 1M-RDI cut-off value of ≥ 50% for sorafenib may be the first factor to predict PFS but not OS in cytokine pretreated mRCC patients. The data indicate that a dose of 400mg/day of sorafenib administered successively for the first one month was necessary to prolong disease stabilisation and could be tolerated by Japanese patients.

Recent topics related to testosterone deficiency syndrome in Japan.

Androgens, the levels of which decrease with ageing, play many physiological roles in various organs. Testosterone deficiency syndrome (TDS) has received widespread attention in the last several years. First-line treatment for TDS should be testosterone replacement therapy (TRT), which is reported to improve several TDS symptoms. Recently, a clinical practice manual for TDS was written and published by a collaborative team from the Japanese Urological Association and the Japanese Society for the Study of the Aging Male to recommend standard procedures for the diagnosis, treatment, prevention and monitoring of adverse reactions to TRT and for post-treatment assessment. In this manual, intramuscular injection of testosterone enanthate or human chorionic gonadotropin and the testosterone gel 'Glowmin' were recommended as TRT. Currently, two topics related to TDS are being focused on in Japan: the relationship between TDS and metabolic syndrome and treatment options for eugonadal patients with TDS symptoms. In this review, the possibility of TRT for metabolic syndrome as well as the relationship between testosterone and adiponectin, which is a key molecule in metabolic syndrome, is discussed. Finally, the possibility of herbal medicines as a treatment option for patients with TDS is addressed, especially for eugonadal patients, because eugonadal men with TDS symptoms account for approximately 30% of the general population. The increase in the levels of several cytokines, such as IL-8, IL-13, interferon-γ and tumor necrosis factor-α, after herbal medicine treatment may be the reason for this efficacy.

Change in cytokine levels after administration of saikokaryuukotsuboreito or testosterone in patients with symptoms of late-onset hypogonadism.

The purpose of this study was to evaluate plasma cytokine levels after treatment with saikokaryukotsuboreito (SKRBT), which is a herbal medicine, or androgen replacement treatment (ART), for patients with late-onset hypogonadism (LOH)-related symptoms. Thirty-one patients over 40 years of age with LOH-related symptoms were included in this study. SKRBT was given orally three times daily to a total of 7.5 g/day for 15 eugonadal patients and ART was give to 16 hypogonadal patients by intramuscular injection of testosterone enanthate at 125 mg each time every 2 weeks. Plasma levels of testosterone and 18 cytokines, as well as LOH-related symptoms scored according to the Aging Males' Symptoms (AMS) scale, were compared before and more than 2 months after treatment. In the ART group, the total AMS score was decreased and testosterone was increased significantly after treatment. No cytokine variables were altered significantly after the treatment. In the SKRBT group, although the total AMS score was significantly decreased, testosterone did not change. From the evaluation of cytokines, a significant increase was found in interleukin (IL)- 8, IL-13, interferon-gamma and tumour necrosis factor-alpha. We conclude that SKRBT might improve LOH-related symptoms in eugonadal patients through the beneficial effect of cytokines, a mechanism that is quite different from ART.

Effect of 1,25-dihydroxyvitamin d on testicular morphology and gene expression in experimental cryptorchid mouse: testis specific cDNA microarray analysis and potential implication in male infertility.

PURPOSE: We evaluated the morphological effect and alterations in gene expression caused by 1,25-dihydroxyvitamin D treatment in the mouse testis undergoing experimental cryptorchidism and subsequent orchiopexy. MATERIALS AND METHODS: The mean modified Johnsen score and testicular weight were estimated after 4 weeks of treatment with a 1,25-dihydroxyvitamin D prodrug. We examined sites of vitamin D receptor and mRNA expression, and 1,25-dihydroxyvitamin D analogue accumulation in the mouse testis. Also, we compared alterations in gene expression in the cryptorchid mouse testis with or without 1,25-dihydroxyvitamin D administration by testis specific cDNA microarray. We confirmed protein synthesis of a candidate among up-regulated genes in primary cultures of Sertoli's cells by Western blotting. RESULTS: Mean +/- SEM Johnsen score and testicular weight were increased by 1,25-dihydroxyvitamin D treatment but not significantly (6.12 +/- 0.33 vs 5.27 +/- 0.4 and 49.3 +/- 3.8 mg vs 42.6 +/- 5.5, p = 0.13 and 0.065, respectively). Vitamin D receptor and its mRNA were positive in Sertoli's cells. The 1,25-dihydroxyvitamin D analogue accumulated mainly in Sertoli's cells. Of 2,483 testis specific genes 19 showed up-regulation by 1,25-dihydroxyvitamin D treatment. Of these genes the regulator of cellular cholesterol homeostasis Abca1 was expressed mainly in Sertoli's cells and influenced male fertility. In primary cultures of Sertoli's cells the synthesis of Abca1 protein was increased by 1,25-dihydroxyvitamin D treatment but not by follicle-stimulating hormone or testosterone treatment. CONCLUSIONS: We noted that 1,25-dihydroxyvitamin D contributes to spermatogenesis by up-regulating certain specific genes in Sertoli's cells. Testis specific cDNA microarray analysis and vitamin D supplementation may have implications for managing male infertility.

Clinical trial of treatment with saikokaryukotsuboreito for eugonadal patients with late-inset hypogonadism-related symptoms.

The purpose of this study was to evaluate the efficacy and safety of saikokaryukotsuboreito (SKRBT), which is widely used for a variety of clinical conditions, neuropsychiatric disorders, for patients with LOH-related symptoms. Twenty-two eugonadal patients over 40 years of age with LOH-related symptoms were included in this study. SKRBT was given orally to these patients three times daily to a total of 7.5 g/day for more than two months. Laboratory and endocrinological profiles were reviewed, and LOH symptoms were judged by means of several health assessment instruments such as the Aging Males' Symptoms (AMS) scale, Self-rated Depression Scale (SDS), International Prostate Symptom Score (IPSS), and King's Health Questionnaire (KHQ). Total AMS scores and AMS subscores were significantly decreased after the treatment. The KHQ, general health perception and impact on life scores were also significantly decreased, although no significant improvement was observed in other KHQ factors or the SDS score or IPSS. The serum concentrations of testosterone fractions did not change with treatment. Laboratory values did not change, and no adverse effects were identified after treatment. We conclude that SKRBT may be considered for treatment of patients with LOH-related symptoms for eugonadal patients.

Differential brain processing of audiovisual sexual stimuli in men: comparative positron emission tomography study of the initiation and maintenance of penile erection during sexual arousal.

The human male psychosexual cycle consists of four phases: excitation, plateau, orgasm, and resolution. Identification of the specific neural substrates of each phase may provide information regarding the brain's pathophysiology of sexual dysfunction. We previously analyzed regional cerebral blood flow (rCBF) with H(2)15O-positron emission tomography (PET) during the excitation phase (initiation of penile erection) induced by audiovisual sexual stimuli (AVSS) and identified activation of the cerebellar vermis, the bilateral extrastriate cortex, and right orbitofrontal cortex, suggesting a role of cognition/emotion in the excitement phase. In the present study, we analyzed rCBF of the same six healthy volunteers during the plateau phase (maintenance of penile erection) induced by AVSS and compared the results with those of the excitation phase. Penile rigidity was monitored in real time with RigiScan Plus during PET scanning. Images were analyzed by statistical parametric mapping (SPM) software, and rCBF in the amygdala, hypothalamus, anterior cingulate, and insula was measured. During the plateau phase, primary subcortical activation was noted in the right ventral putamen, indicating motivational factors in the sexual response via the limbic reward circuit. A significant increase in rCBF in the left hypothalamus was also observed during the plateau phase. The right anterior cingulate and left insula were specifically activated during the excitation phase but not during the plateau phase. These results indicate a significant role of the ventral putamen and the hypothalamus in the plateau phase and confirm that paralimbic and limbic components of the human brain differentially coordinate the sexual response in a psychosexual phase-dependent manner.

Significance of electrostimulation in detecting neurovascular bundle during radical prostatectomy.

OBJECTIVE: The reported rate of erectile dysfunction after nerve-sparing prostatectomy varies according to physicians. Because exact preservation of the neurovascular bundle (NVB) solely depends on the judgment of the physician, he or she should try to correctly identify the NVB and also avoid neurophysiologic injury of the NVB during the procedure. The purpose of the present study is to assess the status of the NVB preservation by physician's judgment at the operation, the changes in intracavernous pressure related to intraoperative electrical stimulation and postoperative histopathological examination. PATIENTS AND METHODS: Thirty-eight patients who underwent nerve-sparing radical prostatectomy judged by intraoperative electrical stimulation of the NVB were included in this study. Bilateral, unilateral and non-nerve-sparing procedures were performed in 18, 17, and 3 cases, respectively. The NVB preservation evaluated by intraoperative physician's judgment was compared to that evaluated by postoperative histopathological examination. Furthermore, the NVB preservation evaluated by intraoperative electrical stimulation was compared to that by physician's judgment and postoperative histopathological examination. RESULTS: For 68 of 76 NVB (89.5%), intraoperative subjective judgment and histopathological assessment were identical. For 66 of 76 NVB (86.8%), electrical stimulation findings and the physician's judgments were identical, and for 70 of 76 NVB (92.1%), electrical stimulation findings and histopathological findings were identical. CONCLUSION: Even if physicians are convinced of a successful nerve-sparing procedure, there are some cases in which the NVB is not preserved accurately or neurophysiological damage is suffered. Therefore, intraoperative electrical stimulation of the NVB as well as the cavernosal nerve is very useful in evaluation of NVB preservation.

Brain processing of audiovisual sexual stimuli inducing penile erection: a positron emission tomography study.

PURPOSE: Penile erection is dependent on commands from the central nervous system. Although basic studies of animals and neuroimaging studies of humans have been conducted to identify key brain regions associated with sexual arousal, to our knowledge no reliable studies of the first excitation phase of sexual arousal leading to penile erection have been reported. MATERIALS AND METHODS: We used H(2)(15)O-positron emission tomography to analyze regional cerebral blood flow just before penile erection in heterosexual volunteers. The subjects viewed 3 different types of audiovisual materials-sexually explicit clips, nonsexual neutral clips and dynamic mosaic image control clips-presented in random order, and penile rigidity was monitored in real time with a RigiScan(R) Plus device. Positron emission tomography scanning was initiated simultaneously when each clip was started, and images obtained when the subjects showed appropriate penile response were analyzed and compared. RESULTS: The advanced audiovisual cortices and cerebellar vermis in the right hemisphere were activated for sexually explicit-dynamic mosaic image control clip contrast, and only the right middle frontal gyrus was activated for sexually explicit- nonsexual neutral clip contrast. Several primary visual and audio regions were activated for dynamic mosaic image control-sexually explicit clip contrast and nonsexual neutral-sexually explicit clip contrast. CONCLUSIONS: We speculate that advanced audiovisual activity with imagination, not primary visual and audio activity, occurs when men experience sexual arousal inducing penile erection. Furthermore, the cerebellar vermis may be a key region for induction of penile erection in humans.