OBJECTIVE:We investigated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) among hypogonadal men with osteopenia/osteoporosis. METHODS:From our previous EARTH study population, 74 patients with a clinical diagnosis of osteopenia or osteoporosis and hypogonadism were included in this study, as the TRT (n = 35) and control (n = 34) groups. The TRT group was administered 250 mg of testosterone enanthate injection every 4 weeks for 12 months. The BMD, waist circumference, body mass index, body fat percentage, and muscle volume were measured at baseline and at 12 months. Blood biochemical data, including total cholesterol, triglycerides, HDL-cholesterol, hemoglobin A1c, and adiponectin values were also evaluated. RESULTS:At the 12-month visit, BMD significantly increased in both groups. However, comparisons on changes of parameter values from baseline to the 12-month visit between the TRT and control groups were significantly different in BMD (5.0 ± 5.0 vs. 3.0 ± 3.2; p = .0434) and in adiponectin value (-0.90 ± 3.33 vs. 0.10 ± 2.04; p = .0192). There were no significant changes in other parameters. CONCLUSIONS:TRT for 12 months could improve BMD with a decrease in adiponectin levels among hypogonadal men with osteopenia/osteoporosis.

Although Vietnam's massive herbicide exposure in 1960s and 1970s was clearly injurious to health, not all causal relationships have been clarified. We therefore explored associations among dioxins, steroid hormones, age and prostate cancer risk in men. We compared serum levels of dioxin, steroid hormones and prostate specific antigen (PSA) in men aged 56–81years from herbicide-exposed hotspots (n=50) with those from non-sprayed regions (n=48). Mean serum levels of dioxin congeners in the hotspot group were 1.5–11.3 times higher than the non-sprayed group depending on specific compound. Levels of testosterone, estradiol and 3β-hydroxysteroid dehydrogenase (3β-HSD) activity in the hotspot group were also significantly higher than in non-sprayed group. Estradiol levels were significantly related to levels of several specific dioxin derivatives in both group. Significant positive correlations were also found between DHT and 1234678-HpCDD or 1234678-HpCDF; and between 3β-HSD activity and 123678-HxCDD, 123478-HxCDF, 123678-HxCDF, or HxCB#169. After adjusting for age, body mass index, and tobacco use, multiple linear regressions showed levels of dihydrotestosterone (DHT), estradiol, testosterone and 3β-HSD activity were not associated with dioxins in the two groups; however, levels of DHT, testosterone and 3β-HSD activity increased significantly with age in the hotspot group. The hotspot and non-sprayed groups did not significantly differ in PSA levels. But six of the hotspot subjects had PSA levels >3ng/mL, 3 of whom were suspected to have prostate cancer (PC) after digital rectal examination. Our findings suggest that dioxin exposure can lead to increased levels of several sex steroid hormones with age. The correlation of dioxin with steroid hormone levels and prostate cancer risk should be studied further.

Abstract This study analyzed the effects of dutasteride on lower urinary tract symptoms based on the association between changes in the total testosterone (TT)/dihydrotestosterone (DHT) levels and total prostate volume (TPV) reduction. Sixty participants diagnosed with benign prostatic hyperplasia were given 0.5 mg of dutasteride daily for 52 weeks. Measures of TT and DHT levels, TPV and uroflowmetry were obtained before and after dutasteride treatment. Forty-three patients demonstrated a TPV reduction of ≥5% (Group 1), whereas the remaining 17 patients demonstrated a TPV reduction of <5% (Group 2). DHT suppression and DHT/TT ratio at baseline were significantly higher in Group 1 than Group 2. International Prostate Symptom Scores (IPSS) and uroflowmetry were significantly improved in both groups. In Group 2, nine patients demonstrated some improvement in IPSS (Group 2A), whereas eight did not (Group 2B). The rate of TT increase and improvement in voiding symptoms were significantly higher in Group 2A than Group 2B. Dutasteride-induced TPV reduction is dependent on individual 5-α reductase inhibitor activity. Some patients demonstrating smaller dutasteride-induced TPV reduction may experience an improvement in voiding symptoms owing to an increased level of testosterone.

Androgen replacement therapy (ART) efficacy on late-onset hypogonadism (LOH) has been widely investigated in Western countries; however, it remains controversial whether ART can improve health and prolong active lifestyles. We prospectively assessed long-term ART effects on the physical and mental statuses of aging men with LOH in Japan. The primary endpoint was health-related quality of life assessed by questionnaires. Secondary endpoints included glycemic control, lipid parameters, blood pressure, waist circumference, body composition, muscular strength, International Prostate Symptom Scores (IPSS), International Index of Erectile Function-5 (IIEF-5) scores, and serum prostate-specific antigen levels. Of the 1637 eligible volunteers, 334 patients > 40 years with LOH were randomly assigned to either the ART (n = 169) or control groups (n = 165). Fifty-two weeks after the initial treatment, ART significantly affected the role physical subdomain of the short form-36 health survey (SF-36) scale (P = 0.0318). ART was also associated with significant decreases in waist circumstance (P = 0.002) and serum triglyceride (TG) (P = 0.013) and with significant increases in whole-body and leg muscle mass volumes (P = 0.071 and 0.0108, respectively), serum hemoglobin (P < 0.001), IPSS voiding subscore (P = 0.0418), and the second question on IIEF-5 (P = 0.0049). There was no significant difference between the groups in terms of severe adverse events. In conclusion, in patients with LOH, long-term ART exerted beneficial effects on Role Physical subdomain of the SF-36 scale, serum TG, waist circumstance, muscle mass volume, voiding subscore of IPSS, and the second question of IIEF-5. We hope our study will contribute to the future development of this area.

Most studies on the relationship between Agent Orange and prostate cancer have focused on US veterans of the Vietnam War. There have been few studies focusing on the relationship between levels of prostate-specific antigen (PSA) and dioxins or steroid hormones in Vietnamese men. In 2009–2011, we collected blood samples from 97 men who had resided in a "dioxin hotspot" and 85 men from a non-sprayed region in Vietnam. Then levels of PSA, dioxins, and steroid hormones were analyzed. Levels of most dioxins, furans, and non-ortho polychlorinated biphenyls were higher in the hotspot than those in the non-sprayed region. Levels of testosterone, dehydroepiandrosterone, and estradiol differed significantly between the hotspot and the non-sprayed region, but there were no correlations between levels of PSA and steroid hormones and dioxins in either of the two regions. Our findings suggest that PSA levels in Vietnamese men are not associated with levels of dioxin or steroid hormones in these two regions.

Abstract Objective: We investigated the effects of testosterone replacement therapy (TRT) on nocturia and general health among men with hypogonadism and nocturia. Methods: From our previous EARTH study population, 64 patients with a clinical diagnosis of nocturia (two or more times per one night) and hypogonadism, comprising the TRT group (n = 31) and controls (n = 33), were included in this analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 6 months. All patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score and Short Form-36 health survey at baseline and 6-month visit. These categories were compared based on changes from baseline to the 6-month visit between TRT and control groups. Results: At the 6-month visit, the TRT group had a significant decrease in IPSS question no. 7 and AMS question no. 4, whereas no significant changes were observed in the control group. Additionally, role limitation because of health program, vitality and mental health domains were significantly improved in the TRT group. Conclusions: Six-month TRT may improve nocturia, sleep conditions and quality of life among men with hypogonadism and nocturia.

We assessed the factors significantly associated with lower urinary tract symptoms (LUTS) in men with late-onset hypogonadism (LOH) syndrome. The study population consisted of 258 patients aged 40 years or older diagnosed with LOH syndrome. Each patient completed a questionnaire study, such as the International Index of Erectile Function (IIEF) 5, Aging Male Score (AMS), and International Prostate Symptom Score (IPSS). Body mass index (BMI), waist size, and muscle volume were measured in all patients, and blood biochemical data, including total cholesterol, triglyceride, hemoglobin A1c, and free testosterone (free T), were also collected. We analyzed the factors that have effect on IPSS. The mean age of the patients was 64.9 ± 8.7 years, and the mean free T value was 7.3 ± 2.2 pg/mL. The critical factors affecting IPSS were IIEF5 score, BMI, muscle volume, age, AMS, and free T-value ( P  < 0.05). Age showed the strongest significant positive correlation with IPSS (r = 0.321, P  < 0.001). Each factor was controlled for age. IIEF5 score and AMS were independent factors affecting IPSS (r = −0.221 and 0.195, respectively, P  < 0.05). IPSS showed an inverse correlation with IIEF5, and a positive correlation with AMS. LUTS also had a weak negative correlation with Free T-value but this was not significant (r = −0.121, P  = 0.061). Lower urinary tract symptoms were significantly correlated with erectile function and psychological symptoms in men with LOH syndrome.

Objectives : To determine testosterone fractions in Japanese men and to compare the values as stratified by age with those of Framingham Heart Study (FHS) subjects. Methods : We enrolled 498 healthy Japanese men. Total testosterone (msTT) was assayed by LC-MS/MS, sex hormone-binding globulin (SHBG) was assayed by immunoassay and free testosterone (cFT) was calculated by a lab at the Boston Medical Center. Analog FT (aFT) and total testosterone (iaTT) were determined by immunoassay. We compared msTT and cFT values in the Japanese subjects with values in the American FHS generation 3 cohort. Results : The mean serum msTT, SHBG and cFT values were 439.4±167 ng/dL, 65.34±30.61 nmol/L and 58.75±20.0 ng/dL, respectively. The correlation coefficients with age for msTT, SHBG and cFT were 0.0010, 0.5041and -0.496, respectively. There were no age-related changes in msTT values in healthy men (P=0.981), while SHBG and cFT levels showed similar age-related changes (P<0.0001). Serum aFT levels (8.24±12.9 pg/mL) showed age-related changes (P<0.0001) regardless of iaTT levels (P=0.828). Serum iaTT values (486.1±1162.5 ng/dL) correlated with serum msTT values (r=0.740 95%CI, 0.6965 to 0.7781, P<0.0001). Similarly, aFT and cFT values showed a highly significant correlation (r=0.706 95%CI, 0.6587 to 0.7473, P<0.0001). The aFT values were approximately 10% of the cFT values. Conclusions : In contrast to the FHS cohort, TT values were not associated with advancing age in this Japanese cohort and cannot be used to diagnose late-onset hypogonadism in Japan. The aFT value is a suitable biochemical determinant for diagnosing late-onset hypogonadism syndrome.

ObjectivesTo determine testosterone fractions in Japanese men and to compare these values with those of Framingham Heart Study participants.MethodsWe enrolled 498 healthy Japanese men. Total testosterone was assayed by liquid chromatography tandem mass spectrometry, sex hormone‐binding globulin was assayed by immunoassay and free testosterone was calculated by a laboratory at the Boston Medical Center. Analog‐based free testosterone and immunoassay‐based total testosterone were determined by immunoassay. We compared mass spectrometry assay‐based total testosterone and calculated free testosterone values in the Japanese participants with values in the American Framingham Heart Study third generation cohort.ResultsThe mean serum mass spectrometry assay‐based total testosterone, sex hormone‐binding globulin, and calculated free testosterone values were 439.4 ± 167 ng/dL, 65.34 ± 30.61 nmol/L, and 58.75 ± 20.0 pg/mL, respectively. The correlation coefficients with age for mass spectrometry assay‐based total testosterone, sex hormone‐binding globulin, and calculated free testosterone were 0.0010, 0.5041, and −0.496, respectively. There were no age‐related changes in mass spectrometry assay‐based total testosterone values in healthy men (P = 0.981), whereas sex hormone‐binding globulin and calculated free testosterone levels showed similar age‐related changes (P < 0.0001). Serum analog‐based free testosterone levels (8.24 ± 2.9 pg/mL) showed age‐related changes (P < 0.0001) regardless of immunoassay‐based total testosterone levels (P = 0.828). Serum immunoassay‐based total testosterone values (486.1 ± 162.5 ng/dL) correlated with serum mass spectrometry assay‐based total testosterone values (r = 0.740, 95% confidence interval 0.6965–0.7781, P < 0.0001). Similarly, analog‐based free testosterone and calculated free testosterone values showed a highly significant correlation (r = 0.706, 95% confidence interval 0.6587–0.7473, P < 0.0001). The analog‐based free testosterone values were approximately 10% of the calculated free testosterone values.ConclusionsIn contrast to the Framingham Heart Study cohort, total testosterone values in Japanese men are not associated with advancing age; thus, they cannot be used to diagnose late‐onset hypogonadism in Japan. The analog‐based free testosterone value can be considered instead as a suitable biochemical determinant for diagnosing late‐onset hypogonadism syndrome.

Introduction: We investigated the effects of the relative increase in testosterone by dutasteride administration in patients with benign prostatic hyperplasia and hypogonadism on urinary symptoms or androgen-responsive general health.Methods: Seventy-six patients were enrolled, and were taking 0.5 mg dutasteride daily for 52 weeks. Before and after treatment, all participants underwent blood test, and body mass index, prostate volume (PV), bone mineral density (BMD), post-voiding residual (PVR) volume, and muscle volume were measured. All patients responded to the questionnaires: International prostatic symptom score (IPSS), Overactive Bladder Symptom score (OABSS). Patients were divided into two groups according to the increase rate of total testosterone (TT): group A, >20% increase in TT level; group B, <20% increase or decrease.Results: Baseline TT and free testosterone (FT) levels were significantly lower in group A than group B. Both groups showed marked improvement in PV and PVR. Group A showed significant improvement in IPSS and OABSS with a significant increase of FT level, whereas group B showed no significant change. Dutasteride treatment contributed to a significant increase in BMD in group A.Conclusions: Dutasteride treatment significantly improved urinary symptoms and BMD in patients with low baseline serum TT and FT levels.

ObjectivesDeletions in the azoospermia factor regions are the most common known molecular genetic cause of human male infertility involving spermatogenetic failure. Testing for these deletions in Japanese DNA samples using conventional sequence‐tagged site probes occasionally lead to considerable non‐specific or faint products in the Japanese population. The aim of the present study was to evaluate the sensitivity and specificity of a newly developed kit for the detection of azoospermia factor microdeletions in the Japanese population.MethodsSequence‐tagged site probes were reselected and the Luminex suspension array assay was carried out. Validation was retrospectively carried out with 2014 DNA sequences with known microdeletions, which were divided into four categories.ResultsCategory 1 deletions that corresponded to the conventional classification of azoospermia factor deletion were present in 83 men (4.2%), which can result in intrachromosomal homologous recombination. Kit data confirmed the presence of deletions of this type in DNA sequences known to harbor the azoospermia factor deletions. Category 2 deletions involved cytogenetic abnormalities in 28 men (1.4%), whereas category 3 deletions in 759 men (37.7%) were atypical classifications including the gr/gr deletion. As these deletions are thought to be a result of palindromic units and non‐homologous recombination, these microdeletions might impact in the interpretation of some clinical findings. The rest of the 1145 cases (56.8%) were assigned to category 4 as normal variants (polymorphism/no deletion).ConclusionsThe present findings show that this new kit offers good sensitivity and specificity with the advantage of saving in terms of cost and time.

An interlaboratory comparison study for melatonin, cortisol and testosterone in saliva in which five laboratories participated is reported in this study. Each laboratory blindly measured eight samples prepared from natural saliva spiked with melatonin, cortisol and testosterone in the range 0-579 pmol/L for melatonin, 0-90 nmol/L for cortisol, and 0-622 pmol/L for testosterone. The recovery of spiked material for melatonin ranged from 91-110%, from 83-100% for cortisol and from 80-94% for testosterone. The content of natural hormone in saliva was estimated to be between 0.278 and 6.90 pmol/L for melatonin, 0.56 and 6.72 nmol/L for cortisol and 11.9 and 73.8 pmol/L for testosterone. This indicates a large interlaboratory variation. The present study emphasizes the importance of external quality control for the analysis of melatonin, cortisol and testosterone in saliva.

Objectives To provide information of semen quality among normal young Japanese men and indicate the frequency of reduced semen quality.Design Cross-sectional, coordinated studies of Japanese young men included from university areas. The men had to be 18-24years, and both the man and his mother had to be born in Japan. Background information was obtained from questionnaires. Standardised and quality-controlled semen analyses were performed, reproductive hormones analysed centrally and results adjusted for confounding factors.Setting Four study centres in Japan (Kawasaki, Osaka, Kanazawa and Nagasaki).Participants 1559 men, median age 21.1years, included during 1999-2003.Outcome measures Semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology and reproductive hormone levels.Results Median sperm concentration was 59 (95% CI 52 to 68) million/ml, and 9% and 31.9% had less than 15 and 40 million/ml, respectively. Median percentage of morphologically normal spermatozoa was 9.6 (8.8 to 10.3)%. Small, but statistically significant, differences were detected for both semen and reproductive hormone variables between men from the four cities. Overall, the semen values were lower than those of a reference population of 792 fertile Japanese men.Conclusions Assuming that the investigated men were representative for young Japanese men, a significant proportion of the population had suboptimal semen quality with reduced fertility potential, and as a group they had lower semen quality than fertile men. However, the definitive roleif anyof low semen quality for subfertility and low fertility rates remain to be investigated.

Genetic mechanisms have been implicated as a cause of some cases of male infertility. Recently, 10 novel genes involved in human spermatogenesis, including human SEPTIN12, were identified by expression microarray analysis of human testicular tissue. Septin12 is a member of the septin family of conserved cytoskeletal GTPases that form heteropolymeric filamentous structures in interphase cells. It is expressed specifically in the testis. Therefore, we hypothesized that mutation or polymorphisms of SEPTIN12 participate in male infertility, especially Sertoli cell-only syndrome (SCOS). To investigate whether SEPTIN12 gene defects are associated with azoospermia caused by SCOS, mutational analysis was performed in 100 Japanese patients by direct sequencing of coding regions. Statistical analysis was performed in patients with SCOS and in 140 healthy control men. No mutations were found in SEPTIN12 ; however, 8 coding single-nucleotide polymorphisms (SNP1-SNP8) could be detected in the patients with SCOS. The genotype and allele frequencies in SNP3, SNP4, and SNP6 were notably higher in the SCOS group than in the control group (P < .001). These results suggest that SEPTIN12 might play a critical role in human spermatogenesis.

Increasing evidence shows a relationship between epigenetic regulation and male infertility. The GTF2A1L gene promoter contains the DNA methylation site of a tissue-specific differentially methylated region (TDMR). Eighty-six patients with non-obstructive azoospermia were assessed for the DNA methylation state of CpG islands in the GTF2A1L promoter using testicular genomic DNA. Based on histological criteria, 26 of the 86 patients had normal spermatogenesis (controls), 17 had hypospermatogenesis and 26 had a Sertoli cell-only phenotype or tubular sclerosis. GTF2A1L TDMR methylation was significantly lower in testes DNA from control samples than from hypospermatogenic samples (P=0.029). Patients with hypospermatogenesis were divided into two subgroups: high DNA methylation (HM, n=5) and low DNA methylation (LM, n=12). The GTF2A1L TDMR methylation rate differed significantly between the HM and LM groups (P=0.0019), and GTF2A1L expression was significantly higher among the LM than in the HM patients (P=0.023). High TDMR methylation was correlated with low GTF2A1L gene expression levels. Both groups demonstrated relatively good outcomes with respect to sperm retrieval, fertilisation, pregnancy and childbirth rates. We observed that aberrant GTF2A1L gene expression was not correlated with fertilisation rates. The testicular sperm extraction (TESE) technique may be used to overcome male infertility due to aberrant TDMR methylation.

Objectives: To establish a base line for future studies on temporal trends, to describe potential geographical differences in semen quality and reference values for studies of men from the general population.Design: Cross-sectional study of fertile men from four areas in Japan. Inclusion criteria were: age 20-45 years at the time of invitation, and both the man and his mother had to be born in Japan. Additionally, the current pregnancy of the female partner had to be achieved by normal sexual relations without any fertility treatment.Setting: Four Japanese study centres at urban areas located in Sapporo, Osaka, Kanazawa and Fukuoka.Participants: 792 men, median age 31.4 years, included from 1999 to 2002.Outcome measures: Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology.Results: Semen volumes, percentages of motile spermatozoa and morphologically normal spermatozoa differed slightly between the four groups, whereas no differences in sperm concentrations or total sperm counts were found. In total, 1.2% of men had a sperm concentration below 5 million/ml, 2.1% below 10 million/ml, 3.5% below 15 million/ml and 16.3% below 40 million/ml. For morphology, 14.7% had less than 5% normal spermatozoa. Reproductive hormone levels varied significantly, however, only little from a biological point of view.Conclusions: This is the first cross-sectional study on semen quality covering fertile men from the major regions of Japan. It showed that semen quality of fertile Japanese men is comparable to that of the best in European regions. The results may serve as reference values for studies of men from the general population.