The effects of advanced paternal age on fertility

Modern societal pressures and expectations over the past several decades have resulted in the tendency for couples to delay conception. While women experience a notable decrease in oocyte production in their late thirties, the effect of age on spermatogenesis is less well described. While there are no known limits to the age at which men can father children, the effects of advanced paternal age are incompletely understood. This review summarizes the current state of knowledge regarding advanced paternal age and its implications on semen quality, reproductive success and offspring health. This review will serve as a guide to physicians in counseling men about the decision to delay paternity and the risks involved with conception later in life.

Physiological normal levels of androgen inhibit proliferation of prostate cancer cells in vitro

For more than 70 years, it has been believed that a severe reduction of serum androgen levels caused regression of prostate cancer （PCa） and that increasing androgen levels enhanced growth of PCa. However, numerous recent studies have questioned this traditional belief. In our study, LNCaP and MDA PCa 2b PCa cells were treated with various levels of androgens for 10 or 20 days, and the cell growth was measured with crystal violet mitogenic assay. The results indicated that the effect of androgens on the proliferation of PCa cells occurs in a biphasic pattern, with the androgen levels promoting optimal cell growth at approximately 0.23 ng m1-1 for LNCaP cells and between I and 2 ng m1-1 for MDA PCa 2b cells. Both of the optimal androgen levels are within the adult men＇s physiological low range （〈2.4 ng ml-1）. At lower concentrations than the optimal androgen level, increasing androgen concentration promoted the proliferation of PCa cells. However, at the higher concentrations, increasing androgen concentration resulted in a dose-dependent proliferative inhibition. We conclude that physiologically normal levels of androgen inhibit the proliferation of PCa cells in vitro. However, at very low levels androgens are essential for initial growth of PCa cells.

Color Doppler ultrasound imaging in varicoceles: Is the difference in venous diameter encountered during Valsalva predictive of palpable varicocele grade?

Objective:The clinical grading system for varicoceles is subjective and dependent on clinician experience.Color Doppler ultrasound(US)has not been standardized in the diagnosis of varicoceles.We aimed to determine if US measurement of varicocele could be predictive of World Health Organization(WHO)varicocele grade.Methods:Men who presented for either scrotal pain or infertility to a tertiary men’s health clinic underwent physical examination,and varicoceles were graded following WHO criteria(0Zsubclinical,1,2,3).US was used to measure largest venous diameter in the pampiniform plexus bilaterally at rest and during Valsalva maneuver.Receiver operator characteristic curve analysis was used to determine if resting diameter,diameter during Valsalva,or change in diameter between at rest and during Valsalva provided the highest sensitivity and specificity for determining clinical grade.Threshold values for diameter were determined from these receiver operator characteristic curves.Results:A total of 102 men(50 with clinical varicocele and 52 with subclinical varicocele)were included.Diameter at rest was the best ultrasonographic discriminator between subclinical and clinical varicoceles(area under the curve[AUC]Z0.67)with a diameter threshold of 3.0 mm(sensitivity 79%,specificity 42%).Diameter during Valsalva had the greatest AUC for determining clinical Grades 1 versus 2(AUCZ0.57)with diameter threshold of 5.7 mm(sensitivity 71%,specificity 33%).For differentiating between Grades 2 and 3,diameter at rest had the greatest AUC of 0.65 with a threshold of 3.6 mm(sensitivity 71%,specificity 58%).Conclusion:Our results corroborate other studies that have shown a weak correlation between US and clinical grading.The use of diameter during Valsalva was less predictive than diameter at rest and was only clinically significant in differentiating between Grade 1 and 2 varicocele.A standardized method for determining clinically relevant varicoceles on US would allow for improved patient counseling and clinical decision-making.

Roles of a metastasis-associated molecule, RTVP-1, in cancer immunosurveillance

Objective: To elucidate distinct functions of a recently identified cancer metastasis-associated molecule, related to testes-specific, vespid, and pathogenesis protein-1 (RTVP-1) in the mammalian immune system. Methods: Immunohistochemical assays and functional analysis on the immune system were performed on RTVP-/- mice and RTVP-1+/+ mice. Protein-protein interaction (PPI) was used to predict the functions of RTVP-1. Results: Abnormal lymphocyte growth kinetics and reduced numbers of CD8+ T cells were revealed in lymph nodes of RTVP-1-/- mice. Expression of phenotypic markers of maturation in bone marrow-derived dendritic cells (DC) was impaired in RTVP-1-/- DC following antigenic stimulation in vitro and RTVP-1-/- DC failed to provide normal CD4+ T cell stimulatory activities in vivo. RTVP-1-/- mice failed to generate normal CTL or antibody responses in vivo after vaccination. In vivo tumor challenge experiments using a mouse cancer cell line demonstrated that the growth rate of subcutaneous tumors in RTVP-1-/- mice was significantly increased and CD8+ T cell infiltration significantly reduced compared to RTVP-1+/+ mice. PPI showed that RTVP-1 protein closely interacted with molecules associated with immune response and cancer metastasis. Conclusion: RTVP-1 might function as a tumor metastasis suppressor and immunosurveillance molecule in cancer.

Systemic Effects of Growth Hormone in Growth Hormone Deficient Adults: A Meta-Analysis of 48 Prospective Studies

Introduction: The use of growth hormone (GH) treatment in GH deficiency (GHD) continues to increase. However, individual controlled trials of the efficacy and safety of GH have involved relatively few patients and yielded variable results. We seek to analyze the overall effect of GH treatment on various parameters by performing a contemporary meta-analysis of the efficacy and safety of GH administration. Methods: Meta-analysis of 48 blinded, placebo controlled, randomized clinical studies of GH treatment in GHD adults published up to June 2011 was performed. Analyzed variables included anthropomorphic measurements (waist-hip ratio (WHR), lean body mass (LBM)/fat free mass (FFM), trunk fat (TrF), total body water (TBW), fat mass (FM), and body mass index (BMI));cardiovascular (CV) parameters (systolic/diastolic blood pressure (SBP, DBP), heart rate (HR), stroke volume (SV), LDL, HDL, total cholesterol (TChol), triglycerides (TG), apolipoprotein B (ApoB), C-reactive protein (CRP));and diabetes parameters (fasting insulin and glucose, hemoglobin A1c (HgbA1c)). Effect sizes (ES) were used to determine significance and weighted mean differences between GH and control were used to quantify size of effect. Results: 2231 adults with growth hormone deficiency were included. Significant beneficial changes resulting from GH administration were observed in the following variables: anthropomorphic—WHR, FM, LBM, FFM, TBW;cardiovascular—LDL, HDL, TChol, ApoB, CRP;significant adverse changes were seen in diabetic parameters—fasting insulin, fasting glucose, and HgbA1c. Compared to prior meta-analyses, larger ESs were observed for LDL, HDL, total cholesterol, fasting insulin and fasting glucose levels. Conclusions: GH administration in GHD adults results in improvement in anthropomorphic parameters, as well as CV parameters, but with worsening of diabetes markers. Data on long-term safety, including on CV effects and malignancy, as well as data assessing the role of GH replacement in combination with testosterone replacement continue to be sparse.

In vitro production of functional sperm in mice

Spermatogenesis refers to the process by which the production and development of the spermatozoa （the mature male gamete of most sexually reproducing species） occurs. It is a complex, stepwise process of sperm development, taking more than a month depending upon the species involving three specific functional phases： spermatogonial proliferation, meiosis and metamorphosis.1 Investigators have been successful in recreating this process in some species of fish; however, this whole process has never been reproduced in vitro in mammals.

In vivo exploration of the functional activity of the non-coding 8q24 prostate cancer risk locus

Genome-wide association studies （GWAS） have successfully identified a substantial number of risk variants for prostate cancer [1-10]. In total, more than 20 single nucleotide polymorphisms （SNPs） that predispose to prostate malignancy have been found scattered throughout the genome in coding and non-coding regions. The 8q24 chromosomal region is an intriguing locus as it harbors five independent susceptibility variants （rs10086908; rs16901979; rs620861; rs6983267; rs1447295） that span a 440-kb genomic interval devoid of genes or protein-coding transcripts.

Semen analysis in 21st century medicine： the need for sperm function testing

Sperm function testing, once commonly performed for the infertile couple before employing assisted reproductive technology （ART）, has fallen out of favour in many reproductive medicine centers throughout the world. Indeed, the most recent addition of the ＇World Health Organisation （WHO） Laboratory Manual for the Examination and Processing of Hu- man Semen＇ now groups many of these procedures into a section termed Research Procedures. In large part, this reflects the current clinical practice of bypassing the in-depth evaluation of the male partner, while assuming that if a spermatozoon can be found for intracytoplasmic sperm injection （ICSI）, it must be a healthy cell capable of achieving fertilization. Never- theless, sperm function testing can provide valuable clinical insights into defects causing male infertility. Admittedly, in some cases, functional sperm deficiencies can be overcome using an ART. In other cases, couples will be empowered by the knowledge of the cause of their infertility, and for some couples, perhaps even the likelihood of ICSI success （relative to the spermatozoa）. The knowledge allows them to make truly informed reproductive decisions, including （perhaps） the de- cision to seek donor insemination, to adopt or to remain childless. Knowledge of the cause of their infertility may provide closure for couples and a sense of confidence regarding their choice of reproductive treatment.

Sperm counts and sperm sex ratio in male infertility patients

In recent years, investigators have noted a trend toward a declining proportion of male births in many industrialized nations. While men bear the sex-determining chromosome, the role of the female partner as it pertains to fertilization or miscarriage may also alter the gender ratio. We attempted to determine a man＇s secondary sex ratio （F1 generation） by directly examining the sex chromosomes of his sperm. We examined our male infertility clinic database for all men who had undergone a semen fluorescence in situ hybridization （FISH）. Patient demographic and semen parameters were recorded. Chi-squared analysis was used to compare gender ratios （Y chromosomes/total chromosomes）. Multivariable logistic regression was used to predict the odds of possessing a Y-bearing sperm after accounting for demographic and semen parameters. A total of 185 men underwent sperm FISH. For the entire cohort, the proportion of Y chromosome-bearing sperm was 51.5%. Men with less than five million motile sperm had a significantly lower proportion of Y chromosome-bearing sperm （50.8%） compared to men with higher sperm counts （51.6%; P= 0.02）. After multivariable adjustment, a higher sperm concentration, total motile sperm count and semen volume significantly increased the odds of having a Y chromosome-bearing sperm （P〈0.01）. As a man＇s sperm production declines, so does the proportion of Y chromosome-bearing sperm. Thus, a man＇s reproductive potential may predict his ability to sire male offspring.

21世纪医学的精液分析:精子功能检测的必要性

精子功能检测曾经是不孕夫妇进行辅助生殖技术(ART)前普遍采取的检查。如今世界各地的生殖医学中心已忽视了这些检查。精子功能检测操作步骤的确已分组纳入最新出版的《世界卫生组织人类精液分析实验室技术手册》的"研究步骤"章节。这很大程度上反映了此现状,即当前临床实践忽略了对不孕夫妇中男方因素的深入检查。认为如果能找到精子,一定就是健康、具有受精能力的、可进行胞浆内单精子注射(ICSI)的精子。然而,通过精子功能测试,可揭示造成男性不育的精子缺陷,为不孕夫妇提供指导。诚然,在某些情况下,ART可克服某些精子功能缺陷,但在其他情况下,夫妇有权了解不孕不育的原因,甚至ICSI的成功率(和精子有关)。知晓这些,有助于其真正清楚自己的生育状态,以证实是否寻求供精人工授精、领养孩子或维持无子女状态。了解不孕的真正原因,有助于说服不孕夫妇放弃艰难又毫无结果的自然妊娠,更加坚定地选择ART治疗不育。

A pathophysiology-based approach to the management ot early priapism

Priapism is a rare condition that involves persistent penile erection for greater than 4 h. Distinct variants exist, each with unique characteristics. Ischemic priapism is a painful medical emergency that may occur as a result of veno-occlusion leading to hypoxia and tissue death. Recurrent bouts of ischemic priapism, or stuttering priapism, require treatment for individual attacks as well as long-term prevention. Non-ischemic priapism is associated with trauma and may be managed conservatively. Recent advances into the pathophysiology of priapism have allowed the development of treatment algorithms that specifically target the mechanisms involved. In this review, we outline the basics of smooth muscle contraction and describe how derangement of these pathways results in priapism. A pathophysiological approach to the treatment of priapism is proposed with duration-based algorithms presented to assist in management.

Counting your sperm before they fertilize： are sperm counts really declining？

Apurported global decline in sperm counts has been a source of controversy since the early 1990s. Numerous studies performed since then, as well as reanalysis of the original data, show either no changes, or even increases, in sperm concentrations over time. In this review, we discuss the 1992 meta-analysis that initiated the continuing debate on whether sperm concentrations are declining, and the com- munity discussion surrounding it over the past two decades. We also highlight studies evaluating sperm concentrations performed since the initial study that produced different results, and conclude that no definitive cause for a decrease in sperm counts has been established, and the effects of geography and environment on sperm counts are unclear.

Men with a complete absence of normal sperm morphology exhibit high rates of success without assisted reproduction

In couples with infertility, abnormal strict morphology of 0% normal forms （NF） is a criterion to proceed rapidly to in vitro fertilization （IVF）. Since no data currently exist, we investigated the outcomes for men with 0% NF to determine reproductive success without the use of assisted reproductive technologies （ART）. A cohort of 24 men with 0% NF were identified （2010-2013） with 27 randomly selected men with 〉4% NF as controls. Patient charts were reviewed with men contacted and administered an Institutional Review Board （IRB）-approved telephone questionnaire to ascertain outcomes. After a median follow-up time of 2.5 years, 29.2% of men with 0% NF did not require ART for their first pregnancy （controls = 55.6%, P〈 0.05）. When all pregnancies were analyzed together, men with 0% NF achieved twenty pregnancies of which 75% did not require IVF （controls - thirty pregnancies; 76.7% did not require IVF）. The average age of men and female partners was similar between men with 0% NF and 〉4% NF. All men had normal follicle-stimulating hormone （FSH）, testosterone, prolactin, sex hormone-binding globulin （SHBG）, and estradiol. Although, global semen parameters were worse in men with 0% NF, when a first pregnancy was a natural conception （NC）, 100% of men with 0% NF （n = 7/7） and 37.5% of controls in = 3/8） went on to have a subsequent pregnancy via NC. Men with 0% NF conceived without IVF in 29.2% of cases compared to 55.6% of controls. Strict morphology should not be used to predict fertilization, pregnancy, or live birth potential. In men with 0% NF, alternative modalities should be considered before immediate IVF.

Varicocele management in the era of in vitro fertilization/intracytoplasmic sperm injection

Varicocele is the most common surgically treatable cause of male infertility, and often results in alterations in semen parameters, sperm DNA damage, and changes to the seminal milieu. Varicocele repair can result in improvement in these parameters in the majority of men with clinical varicocele; data supporting repair in men with subclinical varicocele are less definitive. In couples seeking fertility using assisted reproductive technologies （ARTs）, varicocele repair may offer improvement in semen parameters and sperm health that can increase the likelihood of successful fertilization using techniques such as in vitro fertilization （IVF） or intracytoplasmic sperm injection （ICSI）, or may decrease the level of ART needed to achieve successful pregnancy. Male infertility is an indicator of general male health, and evaluation of the infertile male with an eye toward future health can facilitate optimal screening and treatment of these men. Furthermore, varicocele may represent a progressive lesion, offering an argument for its repair, although this is currently unclear.

Recent advances in the genetics of testicular failure

Infertility affects approximately 15% of couples, and male factor is responsible for 30%-50% of all infertility. The most severe form of male infertility is testicular failure, and the typical phenotype of testicular failure is severely impaired spermatogenesis resulting in azoospermia or severe oligozoospermia. Although the etiology of testicular failure remains poorly understood, genetic factor typically is an underlying cause. Modern assisted reproductive techniques have revolutionized the treatment of male factor infertility, allowing biological fatherhood to be achieved by many men who would otherwise have been unable to become father to their children through natural conception. Therefore, identifying genetic abnormalities in male is critical because of the potential risk of transmission of genetic abnormalities to the offspring. Recently, along with other intense researches ongoing, whole-genome approaches have been used increasingly in the genetic studies of male infertility. In this review, we focus on the genetics of testicular failure and provide an update on the advances in the study of genetics of male infertility.Infertility affects approximately 15% of couples, and male factor is responsible for 30%-50% of all infertility. The most severe form of male infertility is testicular failure, and the typical phenotype of testicular failure is severely impaired spermatogenesis resulting in azoospermia or severe oligozoospermia. Although the etiology of testicular failure remains poorly understood, genetic factor typically is an underlying cause. Modern assisted reproductive techniques have revolutionized the treatment of male factor infertility, allowing biological fatherhood to be achieved by many men who would otherwise have been unable to become father to their children through natural conception. Therefore, identifying genetic abnormalities in male is critical because of the potential risk of transmission of genetic abnormalities to the offspring. Recently, along with other intense researches ongoing, whole-genome approaches have been used increasingly in the genetic studies of male infertility. In this review, we focus on the genetics of testicular failure and provide an update on the advances in the study of genetics of male infertility.

Combined tests of prostate specific antigen and testosterone will improve diagnosis and monitoring the progression of prostate cancer

Prostate-specific antigen （PSA） testing has been widely used to screen men for prostate cancer （PCa） and to monitor PCa progression. However, more studies have shown that around 15% of men with low or normal PSA levels have PCa. In this study, we aimed to investigate the relationship of androgen and PSA levels and to better understand the reason that some PCa patients have low serum PSA values. The in vitro data demonstrated that cultured LNCaP cells ceased to produce PSA after androgen withdrawal and resumed PSA production after androgen was re-added. The in vivo experiment results showed that 48% of PCa xenografts carrying mice have serum PSA level lower than 4 ng ml^-1. The serum PSA levels increased significantly with rises in testosterone （T） levels 1 week after T pellet implantation. These data indicated that the androgen is a key factor controlling the production of PSA. Low serum PSA levels in mice with PCa xenografts are associated with low serum T levels. Raising serum T levels in tumor caring mice will also significantly increase serum PSA level. This may have clinical implications when screening PSA in men, who have occult PCa.

Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis disease versus congenital bilateral absence of the vas deferens

Recent data suggest that cystic fibrosis transmembrane conductance regulator(CFTR)gene alterations negatively impact male fertility beyond obstruction.We sought to compare gene alterations,sperm retrieval rates,and intracytoplasmic sperm injection(ICSI)outcomes among men with cystic fibrosis(CF)disease and congenital bilateral absence of the vas deferens(CBAVD)only.We retrospectively evaluated all men who underwent surgical sperm retrieval at two academic,high-volume andrology centers from 2010 to 2018.Only men with documented CFTR alterations and obstructive azoospermia from either CBAVD or CF were included.Differences between groups for CFTR abnormality,sperm retrieval,and ICSI outcomes were statistically analyzed.Overall,39 patients were included with 10 in the CF and 29 in the CBAVD groups.Surgical sperm retrieval rates were significantly lower in the CF group for sperm concentration(14.8×10^(6)ml^(-1)vs 61.4×10^(6)ml^(−1),P=0.02)and total motile sperm count(2.9 million vs 11.4 million,P=0.01).This difference was only predicted by homozygous delta F508 CFTR mutations(P<0.05).The CF group also demonstrated a significantly higher rate of rescue testicular sperm extraction(70.0%vs 27.6%,P<0.03)and lower fertilization rate with ICSI(32.5%vs 68.9%,P<0.01).In conclusion,those with CF demonstrated lower sperm quality,greater difficulty with sperm retrieval,and worse ICSI outcomes compared with CBAVD-only patients.Homozygous delta F508 CFTR mutations appear to significantly impair spermatogenesis and sperm function.

The importance of understanding baseline reproductive function prior to the administration of exogenous testosterone

Recent increases in the awareness of hypogonadism as a clinical condition have led to more men being managed with testosterone supplementation therapy （TST）. While highly effective at raising serum testosterone levels and controlling the symptoms of hypogonadism such as fatigue and low energy,1 the resultant suppression of the hypothalamic-pituitary-gonadal axis can lead to an inhibition of gonadotropins, including follicle-stimulating hormone （FSH） and luteinizing hormone （LH） and subsequent azoospermia.

Are genetic biomarkers the future of male fertility testing？

Men with infertility are subjected to numerous diagnostic tests in attempts to determine the nature of their condition. Initially, medical, surgical, and birth histories are elicited with investigations including semen analyses, hormonal panels, and imaging studies such as scrotal or trans-rectal ultrasounds. In cases of men with nonobstructive azoospermia （NOA）, these inquiries may all return normal results. More specific testing involving karyotyping and Y-chromosome microdeletion analysis are then performed.

The importance of sexual function in men with spinal cord injuries

Spinal cord injuries （SCIs） are often devastating to patients and their families. In those men young enough to consider families and unfortunate enough to be unable to ejaculate, multiple options exist. The attached manuscript by Dr. Ibrahim et al. contains a detailed outline of a multitude of techniques available to the Andrologist to both evoke ejaculation and harvest sperm from these patients. The authors, pioneers in the field of male fertility research for SCI patients, detail very high success rates for penile vibratory stimulation （86% success if above T10, 15% if below） and electroejaculation （91.9% success）.