Teruaki Iwamoto

Spermatogenic ability is different among males in different Y chromosome lineage

AbstractIt is a controversial question whether sperm concentrations in humans are changing. Several researchers have reported on environmental factors affecting sperm quality, but the influence of genetic factors is still not fully understood. In this study, we examined the relationship between Y chromosome haplotypes and sperm concentration in fertile males. In addition, we determined the haplotypes of azoospermic patients. The results show that the mean sperm concentration correlates with Y chromosome type. Moreover, the occurrence of azoospermia is related to one particular Y chromosome lineage. Thus, males with a certain haplotype are at a disadvantage for fathering children. The difference of spermatogenic ability among men is important not only in pursuing male competition as in the past but also as relates to the future of modern human males.

Delayed testosterone replacement restores nitric oxide synthase-containing nerve fibres and the erectile response in rat penis

Objective To elucidate the effect of testosterone on penile innervation.

Androgen replacement therapy contributes to improving lower urinary tract symptoms in patients with hypogonadism and benign prostate hypertrophy: a randomised controlled study.

Purpose. We performed a randomised controlled study regarding the effects of androgen replacement therapy (ART) on lower urinary tract symptoms (LUTS) in hypogonadal men with benign prostate hypertrophy (BPH). Methods. Fifty-two patients with hypogonadism and BPH were randomly assigned to receive testosterone (ART group) as 250 mg of testosterone enanthate every 4 weeks or to the untreated control group. We compared International Prostate Symptom Score (IPSS), uroflowmetry data, post-voiding residual volume (PVR) and systemic muscle volume at baseline and 12 months after treatment. Results. Forty-six patients (ART group, n = 23; control, n = 23) were included in the analysis. At the 12-month visit, IPSS showed a significant decrease compared with baseline in the ART group (15.7 ± 8.7 vs. 12.5 ± 9.5; p < 0.05). No significant changes were observed in the control group. The ART group also showed improvement in maximum flow rate and voided volume (p < 0.05), whereas no significant improvements were observed in the controls. PVR showed no significant changes in either group. In addition, the ART group showed significant enhancement of mean muscle volume (p < 0.05), whereas no significant changes were seen in the controls. Conclusion. ART improved LUTS in hypogonadal men with mild BPH.

The Y Chromosome Region Essential for Spermatogenesis

We analyzed DNA from 153 Japanese men with azoospermia or severe oligozoospermia whose Y chromosomes were cytogenetically normal. A total of 23 loci on the Y chromosome were examined: 15 loci within interval 6 including YRRM1 and DAZ, and 8 loci outside interval 6. Microdeletions were observed in 20 individuals. All deletions involved at least one locus within interval 6. The YRRM1 gene deletion was found in 4 patients, of whom 2 also lacked the SMCY gene. The remaining 16 individuals shared the absence of 10 loci between DYS7C and DYS239 including the DAZ gene. Among them, 13 were azoospermic while 3 showed a little sperm production, indicating that the common deletion resulted in phenotypic diversity. Since there is no region commonly deleted in all patients, azoospermia caused by deletion of the Y chromosome long arm may be genetically heterogeneous.

Effect of testosterone on the number of NADPH diaphorase-stained nerve fibers in the rat corpus cavernosum and dorsal nerve.

OBJECTIVES To elucidate the effect of testosterone on penile nerve supply. METHODS Three groups of 10 rats each were assessed; two groups were castrated and the third underwent a sham operation (control). After castration, one group received subcutaneous injection of testosterone while the others received sesame oil. At 8 weeks, the rats underwent a functional analysis. The evaluation included a subcutaneous injection with apomorphine to study centrally mediated erection, and cavernous nerve electrostimulation and papaverine injection to study peripherally mediated erection. At death, a penile midshaft specimen was taken for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining. RESULTS In the apomorphine study, castrated rats had no erections, but the erectile function of those receiving testosterone was restored to the level of the controls. The mean numbers of NADPH-diaphorase-stained nerve fibers in the copora cavernosa and both dorsal nerves of castrated rats, at 165.8 +/- 20.0 and 271.3 +/- 21.1, respectively, were significantly lower than those of the controls, at 271.7 +/- 14.6 and 471.2 +/- 27.6, respectively. Those of the testosterone replacement group, at 290.7 +/- 10.1 and 500.7 +/- 23.9, respectively, recovered to the control level. The intracavernosal pressure decreased significantly in the absence of testosterone, both after electrostimulation and intracavernosal papaverine injection, and recovered to the control level after testosterone replacement. CONCLUSIONS Our results indicate that testosterone acts on the nervous system to mediate erection. When it is absent, there may be downregulation of both the production and activity of nitric oxide (NO), thereby decreasing the response to peripheral stimulation via the NO pathway. Testosterone replacement may upregulate NO activity to the control level.

Molecular Characterization of Heat Shock-Like Factor Encoded on the Human Y Chromosome, and Implications for Male Infertility

Abstract Azoospermia and oligospermia are major causes of male infertility. Some genes located on the Y chromosome are suggested as candidates. Recently, HSFY, which is similar to the HSF (heat shock transcription factor) family, has been mapped on the human Y chromosome as multicopies. However, newly available sequence data deposited at NCBI shows that only the HSFY gene located on Yq has a long open reading frame containing a HSF-type DNA-binding domain. HSFY is similar to LW-1 on the human X chromosome and a murine HSFY-like sequence (mHSFYL), 4933413G11Rik, on the mouse chromosome 1. LW-1 and mHSFYL have 53% and 70% homology to HSFY for amino acid sequences of their presumed DNA-binding domains, respectively. Comparison of the presumed DNA-binding domains unveiled that the three HSF-like factors, HSFY, LW-1, and mHSFYL, belong to a different class than conventional HSFs. When we screened for deletions on the Yq of males suffering from infertility, we found that HSFY was involved in interstitial deletions on the Y chromosomes for two azoospermic males who had DBY, USP9Y, and DAZ but did not have RBMY located on the AZFb. Expression analysis of HSFY, LW-1, and mHSFYL unveiled that they are expressed predominantly in testis. Furthermore, immunhistochemistry of HSFY in testis showed that its expression is restricted to both Sertoli cells and spermatogenic cells and that it exhibits a stage-dependent translocation from the cytoplasm to the nucleus in spermatogenetic cells during spermatogenesis. These results may suggest that deletion of HSFY is involved in azoospermia or oligospermia.

Clinical Practice Manual for Late-onset Hypogonadism Syndrome

With the aging of the population, the quality of life (QOL) of middleaged and elderly men has come into question and it has been taken up from an interdisciplinary standpoint in recent years. Partial androgen deficiency of the aging male (PADAM) or lateonset hypogonadism (LOH) is a syndrome consisting of symptoms caused by partial deficiency of androgens, but the time of onset varies and the epidemiological status is unclear. Therefore, in Japan to date, this syndrome has been considered as a general phenomenon associated with aging, the medical authorities have not reacted and patients are not being treated. In Western countries however, this phenomenon has attracted attention in relation to geriatrics and reproductive endocrinology since the 1980s. In 1998, the International Society for the Study of the Aging Male (ISSAM) was founded to conduct basic and clinical research, to provide postgraduate education and to engage in publicity activities for the enlightenment of the public. The social background is characterized by the appearance of a very rapidly aging society with longer average life spans. The importance of improving the health of the elderly and preventive medicine as government policy has increased. Improving the health of the elderly not only promotes self-reliance of the elderly but also increases the work force. A high QOL is also possible. The main topic for healthcare in the 21st century is how to maintain the QOL of the elderly. In women, hormone replacement therapy (HRT) is widely applied internationally, but specific healthcare for elderly men appears to be limited to the widespread use of phosphodiesterase type 5 (PDE5) inhibitors to treat erectile dysfunction (ED). Although the delay in healthcare policies for elderly men is not a direct reason, a large gap has appeared between the average life spans of men and women in recent years and in Japan, men have a shorter life span than women by about seven years. In response to this sense of crisis, the World Health Organization (WHO) issued the Geneva Manifesto in 1997 and ‘healthy aging for men’ became an international movement. ISSAM was established in 1998 with the goal of ‘aging male research on gender specific issues in male health’. The first meeting of the society in Asia was held in Malaysia in 2001 and this topic was adopted on an international level from an early stage. The reason appeared to be strong economic and social concern that Asian countries with a current pyramid-type population distribution will become aging societies with a lower birth rate than in developing countries. Japan has already become an aging society with a low birth rate. In the national census (summary) in 2005, the elderly population of 65 years and older accounted for about 21% of the total population, the highest in the developed world. In Japan, scientific research on the aging male started at about the same time as in the rest of Asia, and the Japanese Society for the Study of the Aging Male (JSSAM) was founded in November 2001 with Yoshiaki Kumamoto, professor emeritus of Sapporo Medical University, and Hajime Nawata, professor of Kyushu University as representative facilitators. The goal of this society is ‘undertaking basic, clinical and social research and surveys on policies for the diagnosis, treatment and prevention of male-specific medical problems, and contributing widely to men’s health by development, promotion and spread of proper healthcare’. As mentioned above, the concept of research on the aging male is being promoted as ‘healthy aging for men’ but almost no actual treatment for such patients has been performed. When the JSSAM was established , so-called ‘male climacteric symptoms’ or ‘male menopause’ was popular in the media, and when such treatment was started , many patients mainly with a chief complaint of climacteric symptoms appeared in medical practice. These patients included many with psychiatric problems such as depression and considerable confusion arose in clinics and hospitals. Based on this background , the Subcommittee on Endocrinology, Reproductive Function and Sexual Function of the Japanese Urological Association asked the Scientific Committee to prepare a clinical practice guideline, and a working group was organized to prepare the guideline by a collaborative team from the Japanese Urological Association and JSSAM after a review by the Board of Directors. In this clinical practice manual, the term ‘late–onset hypogonadism (abbreviation: LOH)’ syndrome was adopted as the term that best expresses this condition medically. In order to recommend standard procedures for diagnosis, treatment, prevention and monitoring of adverse reactions due to androgen replacement therapy (ART) and post-treatment assessments, a literature survey of clinical papers was performed , but since treatment of LOH Syndrome has just started , almost all papers had a low recommendation rank. Therefore, the name was changed to ‘Clinical Practice Manual for Treatment of Late-onset Hypogonadism (LOH) Syndrome’ (‘Manual’ hereinafter) instead of the initially planned ‘clinical practice guideline’. Care of LOH Syndrome is in its initial stages and such treatment requires careful consideration. Since many men visiting medical institutions at present complain of ‘climacteric symptoms’, measures must be taken to have this disease recognized in the mental health field. In the future, it will be necessary to establish evidence for treatment of LOH Syndrome from the broad perspective of promotion of ‘healthy aging for men.’ This ‘Manual’ is the first edition aimed at gathering evidence through future diagnosis and treatment of LOH and it is hoped that it will serve as a reference for routine medical practice. Correspondence: Eitetsu Koh MD, Department of Urology, Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa 920-8641, Japan. Email: kohei@med.kanazawa-u.ac.jp This is an English translation of text originally published in Japanese in (LOH ) , 2007, Jihou

Physiological roles of semenogelin I and zinc in sperm motility and semen coagulation on ejaculation in humans

At ejaculation, human sperm are considered to be mechanically trapped and become immotile in the semen coagulum by binding to semenogelins (Sgs) from the seminal vesicle and zinc ions from the prostate. However, the physiological combined roles of the protein and heavy metal on sperm motility are unknown. Here, we have first demonstrated that Sg I alone, which does not form the semen coagulum without zinc, is an inhibitor of the motility of intact human sperm at physiological concentration. On the other hand, zinc ions alone had no effect on sperm motility, but confer recovery of sperm motility that has been inhibited by Sg I at a concentration equal to or less than 1 mg/ml. These observations suggest that the roles played by Sg I and zinc on sperm motility are not mechanical but physiological. Quartz crystal microbalance analysis suggests that the sperm extract first bind to Sg I and then zinc ions which subsequently increase the protein accumulation, suggesting that Sgs inhibit sperm motility by directly binding to the sperm surface. Further accumulation of Sg I mediated by zinc ions may entrap the quiescent sperm at semen ejaculation.

Testosterone replacement therapy by testosterone ointment relieves lower urinary tract symptoms in late onset hypogonadism patients.

Introduction. Patients with late onset hypogonadism (LOH) also suffered from lower urinary tract symptoms (LUTS) and LOH symptoms. The objects of this study are to evaluate the efficacy of testosterone replace therapy (TRT) by testosterone ointment (Glowmin: GL) for LUTS in LOH patients. Methods. The Aging Male Symptom (AMS) scale, Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF-36), International Index of Erectile Function (IIEF-5) and the International Prostate Symptom Score (IPSS) were obtained from patients with LOH. A total of 41 patients with LOH have been treated with TRT using 6 mg/day of GL for 3 months. Serum free testosterone levels (FT) and these four scores were compared before and after TRT. Results. Serum FT levels and the scores for the four parameters of AMS, six of eight domains in SF-36, IIEF-5 and total IPSS improved significantly after 3 months TRT. In addition, all IPSS domains also improved significantly, and voiding disturbance seems to have improved more than storage disturbance (P = 0.0280 vs. 0.0483). Conclusion. TRT by administration of GL is considered to be effective in the improvement of not only ED and LOH symptoms, but also LUTS (especially voiding disturbance) of patients with LOH.

Xenografting of testicular tissue from an infant human donor results in accelerated testicular maturation

BACKGROUND Grafting of testicular tissue into immunodeficient mice has been used to differentiate the neonatal testes from different animal species up to the level of complete spermatogenesis; however, this approach has not been successful for human testicular tissue. The aim of this study was to evaluate the capacity for differentiation of infant human testicular tissue grafts. METHODS AND RESULTS Testicular tissue from a 3-month-old patient with testicular cancer was grafted into immunodeficient nude mice. At the time of grafting, A spermatogonia were the only germ cells present in the testicular tissue. B spermatogonia and first spermatocytes were observed at 7 months and 1 year after grafting, respectively. Positive immunostaining with antibodies against BOULE and CDC25A suggested that spermatocytes in the graft were not arrested but in meiosis. Furthermore, ultrastructural and immunohistochemical analyses showed that the onset of both Sertoli cell maturation and partial differentiation of Leydig cells preceded the appearance of spermatocytes. Differentiation of testicular cells was accelerated compared with in vivo development. CONCLUSIONS Spermatogenesis in the xenograft of infant human testicular tissues proceeded successfully from the stage of spermatogonial stem cells until pachytene spermatocyte formation. The differentiation of Sertoli cells and Leydig cells was reproduced in a manner similar to that in normal testicular development. Grafting of infant human testicular tissue may be a powerful tool to examine the early period of human spermatogenesis and may pave the way for fertility preservation among infant patients.