Leptin and varicocele-related spermatogenesis dysfunction: animal experiment and clinical study

The objective of this study was to explore the relationships between varicocele-related spermatogenesis dysfunction and the expression of leptin and leptin receptors. In rats with experimental varicocele, the function of spermatogenesis, the expression of leptin and leptin receptors in testes were analysed; and in patients with varicocele-related male infertility, serum and seminal plasma levels of leptin, gonadal hormones and semen parameters were evaluated. In the testes of rats, leptin was expressed in seminiferous tubules and intersitium, leptin receptor was predominantly expressed in interstitium. The expression of leptin and its receptor in the testis of rats was not related to the weight of rat, but was inversely related to the weight of testis (r = -0.408, p = 0.009 and r = -0.433, p = 0.005, respectively), the Johnsen scores (r = -0.916, p = 0.000 and r = -0.863, p = 0.000, respectively), the seminiferous tubules diameter (r = -0.853, p = 0.000 and r = -0.870, p = 0.000, respectively) and the thickness of seminiferous epithelium (r = -0.929, p = 0.000 and r = -0.948, p = 0.000, respectively). In varicocele patients (N = 40), the sperm concentration and motility were significantly lower (p = 0.000) than those in the control group (N = 25), and the leptin level in seminal plasma was significantly higher (p = 0.000) than that in the control group. The leptin in serum and seminal plasma was positively related (r = 0.223, p = 0.002). The seminal plasma leptin level was inversely related to sperm concentration (r = -0.632, p = 0.000) and motility (r = -0.635, p = 0.000). There was no significant relation between serum leptin and seminal parameters and between leptin and gonadal hormone values. The dysfunction of spermatogenesis in varicocele-related infertile male is associated with increase in leptin and leptin receptors. Leptin may have local effects on the function of testis and spermatogenesis.     

Leptin levels in infertile male patients are correlated with inhibin B, testosterone and SHBG but not with sperm characteristics

In the present study, differences in leptin levels between different groups of male patients presenting with infertility problems and possible correlations between leptin levels and clinical, spermiological, histological and hormonal characteristics were examined. Two hundred and ten male partners from infertile couples were included in the study. Based on clinical examination, spermiogram and testicular histology results, patients were divided into four groups: 42 men with non-obstructive azoospermia, 15 men with obstructive azoospermia, 68 men with oligoasthenoteratozoospermia and 85 men with normozoospermia. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, testosterone, sex hormone binding globulin (SHBG) and leptin were measured. After adjustment for body mass index, there was a negative correlation between serum levels of leptin and inhibin B, total testosterone and SHBG (r = -0.189, p = 0.009, r = -0.250, p = 0.001 and r =-0.221, p = 0.003 respectively) but there was no correlation between leptin and classical sperm characteristics. Our results therefore demonstrate a link between leptin and testicular function, independently of FSH and LH, possibly involving testosterone and SHBG through a regulation of Leydig cell function.     

Age-related disease pattern in infertile men: increasing incidence of infections in older patients

In a cross-sectional retrospective study, the age-dependency of semen parameters of men with specific andrological diseases was investigated in 3,698 men (mean age 33 years; range 19-63 years) attending a tertiary referral clinic for couple infertility. In all, 1,853 patients suffered from idiopathic infertility (mean age 33.2 years; range 19-60 years), 388 from infections of the accessory glands (34.2; 20-61), 363 had a history of maldescended testes (32.0; 20-51) and 833 a varicocele (33.6; 20-63). In 172 patients, a varicocele and an infection (34.3; 24-54) and in 94 a varicocele and a history of maldecended testes (32.5; 21-53) were found. Semen analysis was performed according to WHO criteria. An age-related decrease in testicular volume was not observed in any group. Total sperm count decreased significantly with advancing age only in patients with an infection of the accessory glands. We found no evidence for age-dependent progressive deterioration of semen variables in the other groups. It may be concluded that the causes for the spermatogenetic defects in men with idiopathic infertility, a history of maldescended testes or varicocele are acquired before adolescence and do not progress during adulthood. In contrast, infections of the accessory glands may lead to decreased sperm counts by functional impairment or partial occlusion of the seminal ducts. Thus, if in the general population declining sperm counts are observed, genital tract infections may be suspected as a contributing factor.     

Impact of weight loss on sperm DNA integrity in obese men

The objective of the study was to determine whether weight loss in obese men improves their fertility with respect to DNA fragmentation index and morphology. Collected fertility parameters included DFI and morphology. Body mass index (BMI) was calculated for all patients with comparisons to their fertility parameters before and after weight loss using paired t test and chi‐square tests. The mean BMI was significantly higher in group 1, before weight loss (33.18 kg/m²), than in group 2, after weight loss (30.43 kg/m²). Overall, 53.3% of men had DFI <20% while 43.8% had a DFI between 20% and 40%, and 2.9% of men had DFI >40%. The mean DFI of participants was higher before weight loss (20.2%) and had improved significantly after weight loss (17.5%) (p = <.001). The weight loss had significant positive correlation with percentage of DFI. There was a significant improvement in morphology after weight loss (p = <.05). In one of the largest cohorts of male fertility and obesity, DFI and morphology demonstrated significant relationship with adiposity, possibly contributing to subfertility in this population.     

中国乙型肝炎和非肝炎男性间的精液质量和辅助生殖技术治疗结果的比较

本研究旨在确定乙型肝炎病毒（HBV）感染对精子质量和辅助生殖技术治疗结局的影响。分析2008年1月至2009年12月于浙江大学附属妇产科医院寻求辅助生育治疗的916例男性（457例乙型肝炎病毒携带者和459例阴性对照男性）的精液参数;将2004年1月至2009年12月期间的男性乙肝病毒携带的587个常规体外受精（In vitro fertilisation,IVF）周期和325个单精子卵细胞浆内注射（Intracytoplasmic sperm injection,ICSI）周期作为阳性观察组,根据取卵日期、女方年龄及ART受精方式通过统计软件以1：1比例匹配,设立夫妇双方均为HBsAg阴性的对照组（587个IVF周期,324个ICSI周期）,分析两组间的辅助生殖治疗结局。与对照组相比,乙肝携带者表现有较低的精液体积、精子总数以及较差的精子活动力和形态学表现（P〈0．05）;乙肝男性夫妇接受ICSI治疗后,双原核（2PN）受精率、优质胚胎率、胚胎着床率以及临床妊娠率均显著性降低俨〈0．05）;而两组病人间的IVF治疗结局差异无显著性（P〉0．05）。通过Logistic回归分析发现乙肝病毒感染作为一个独立的因素增加少弱精子症的发生以及降低ICSI治疗周期的胚胎着床率和临床妊娠率（P〈0．05）。我们的研究结果提示了男性乙型肝炎病毒感染与较差的精子质量和ICSI治疗结局有关,而对IVF治疗结局没有明显的影响。     

Clinical significance of reactive oxygen species in semen of infertile Indian men

Reactive oxygen species (ROS) levels in semen are believed to play both physiological and pathological roles in male fertility. The study was aimed to find the clinical significance of ROS levels in infertile Indian men. This pilot study included 33 idiopathic infertile men and 18 proven fertile controls. ROS levels in the washed sperm were measured using chemiluminescence assay and expressed as 10⁶ cpm per 20 million spermatozoa. Sperm count, percent sperm motility, and percent normal sperm morphology were found to be significantly ( P  < 0.0001) reduced in infertile men compared with the controls. Median (minimum, maximum range) ROS levels of the infertile group [24.90 (6.89, 44.71)] were found to be significantly ( P  < 0.0001) elevated compared with the fertile controls [0.167(0.15, 2.78)]. No significant correlation was seen between ROS levels and semen parameters. Elevated ROS levels in the idiopathic Indian infertile men may be one of the underlying reasons for impaired fertility. Therefore measurement of seminal ROS levels may be used in Indian infertile men for better understanding of the aetiology and selection of antioxidant regimen in the treatment of male infertility. However, large studies may be urgently warranted to find out the role of antioxidants in ROS elevated Indian infertile men through randomised, controlled clinical study.     

Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility

To study the major differences in the distribution of spermatozoa proteins in infertile men with varicocele by comparative proteomics and validation of their level of expression. The study-specific estimates for each varicocele outcome were combined to identify the proteins involved in varicocele-associated infertility in men irrespective of stage and laterality of their clinical varicocele. Expression levels of 5 key proteins (PKAR1A, AK7, CCT6B, HSPA2, and ODF2) involved in stress response and sperm function including molecular chaperones were validated by Western blotting. Ninety-nine proteins were differentially expressed in the varicocele group. Over 87% of the DEP involved in major energy metabolism and key sperm functions were underexpressed in the varicocele group. Key protein functions affected in the varicocele group were spermatogenesis, sperm motility, and mitochondrial dysfunction, which were further validated by Western blotting, corroborating the proteomics analysis. Varicocele is essentially a state of energy deprivation, hypoxia, and hyperthermia due to impaired blood supply, which is corroborated by down-regulation of lipid metabolism, mitochondrial electron transport chain, and Krebs cycle enzymes. To corroborate the proteomic analysis, expression of the 5 identified proteins of interest was validated by Western blotting. This study contributes toward establishing a biomarker “fingerprint” to assess sperm quality on the basis of molecular parameters.     

Review of the role of leptin in the regulation of male reproductive function

Since discovered in 1994, leptin has been thought to be a pleiotropic hormone that regulates food intake, controls energy balance in the body and influences multiple tissues in the body. Leptin plays an important mediating role in the regulation of neuroendocrine and can transmit the nutritional status signals to the reproductive‐related central nervous system. Many studies have shown that leptin may play an important role in the control of reproductive function. Leptin can act on all levels of the hypothalamus–pituitary–gonadal (HPG) axis and may have local effects on the function of testis and spermatogenesis. Leptin is critical for puberty initiation and can also modulate testosterone synthesis by downregulating cAMP‐dependent activation of steroidogenic genes expressions. Leptin is found to be higher in infertile men than in normal subjects. Yet, the exact role of leptin in the regulation of male reproductive function remains incomplete. The purpose of this review was to summarise the recent research about the biological effects of leptin on male reproductive system. In‐depth study of leptin in reproductive system will help to reveal the pathogenesis of infertility and provide new treatment ideas for human assisted reproductive technology.     

Obesity： modern man＇s fertility nemesis

The obesity pandemic has grown to concerning proportions in recent years, not only in the Western World, but in developing countries as well. The corresponding decrease in male fertility and fecundity may be explained in parallel to obesity, and obesity should be considered as an etiology of male fertility. Studies show that obesity contributes to infertility by reducing semen quality, changing sperm proteomes, contributing to erectile dysfunction, and inducing other physical problems related to obesity. Mechanisms for explaining the effect of obesity on male infertility include abnormal reproductive hormone levels, an increased release of adipose-derived hormones and adipokines associated with obesity, and other physical problems including sleep apnea and increased scrotal temperatures. Recently, genetic factors and markers for an obesity-related infertility have been discovered and may explain the difference between fertile obese and infertile obese men. Treatments are available for not only infertility related to obesity, but also as a treatment for the other comorbidities arising from obesity. Natural weight loss, as well as bariatric surgery are options for obese patients and have shown promising results in restoring fertility and normal hormonal profiles. Therapeutic interventions including aromatase inhibitors, exogenous testosterone replacement therapy and maintenance and regulation of adipose-derived hormones, particularly leptin, may also be able to restore fertility in obese males. Because of the relative unawareness and lack of research in this area, controlled studies should be undertaken and more focus should be given to obesity as an etiolgy of male infertility.     

Prediction of reproductive function recovery after microsurgical varicocelectomy in men from infertile couples: Clinical and laboratory predictors

The objective was to reveal predictors for fertility recovery after varicocelectomy in subfertile men. This retrospective study recruited 93 men with clinical varicocele and pathozoospermia who underwent microsurgical varicocelectomy. Stepwise discriminant analysis was performed to identify predictors of spontaneous pregnancy (SP) after surgery. ‘Clinically significant improvement’ (CSI) following varicocelectomy was defined as an increase in total progressively motile sperm count (TPMSC) by at least 12.5 million (calculated from WHO-2010 reference values). 52% of patients showed CSI, and 28% reported SP after surgery. Patients who reported SP (group II), compared to that remained infertile (group I), were younger (27.3 ± 2.9 versus 30.2 ± 4.2 years; p < .01), had less infertility period (24.1 ± 14.0 versus 44.4 ± 32.9 months; p < .05) and had initially higher TPMSC (median (25% −75%) = 34 (11–67) versus 9.5 (0–33) mln; p < .05). The stepwise discriminant analysis showed that male age (coefficient value = −0.157), total sperm motility (0.024) and postoperative increase in TPMSC (0.010) were the significant predictors of SP. The predictive ability, sensitivity and specificity of the discriminant function were 84%, 87%, 76% respectively. This algorithm can be recommended after varicocelectomy in decision-making on natural conception or the ART protocols usage.     

Chlamydia trachomatis and sperm lipid peroxidation in infertile men

Aim: To relate the presence of anti-Chlamydial trachomatis IgA in semen with sperm lipid membrane peroxidation and changes in seminal parameters. Methods: Semen samples of the male partners of 52 couples assessed for undiagnosed infertility were examined for the presence of IgA antibody against C. trachomatis. The level of sperm membrane lipid peroxidation was estimated by determining the malondialdehyde (MDA) formation. Results: Sperm membrane of infertile males with positive IgA antibodies against C. trachomatis showed a higher level of lipid peroxidation than that of infertile males with negative IgA antibody (P<0.05). There was a positive correlation (P< 0.01) between the level of C. trachomatis antibody and the magnitude of sperm membrane lipid peroxidation. All the other tested semen parameters were found to be similar in the two groups. Conclusion: The activation of immune system by C. trachomatis may promote lipid peroxidation of the sperm membrane. This could be the way by which C. trachomatis a     

Evaluation of trend in semen analysis for 11 years in subjects attending a fertility clinic in India

Aim: The data on semen analysis of subjects attending the Fertility Clinic at NIHFW (National Institute of Health and Family Welfare) Munirka, New Delhi for the last 11 years were analyzed to verify the claims and speculations on declining sperm counts in men. Methods: Approximately 10 % of the records every year starting from 1990 to 2000 (numbering 1176 in total) were randomly selected for analysis. Subjects with azoospermia or severe oligozoospermia were excluded from analysis. Results: The average age of the men attending the infertility clinic was 31.2 years. The average semen volume and sperm count were found to be (2.6 ±0.1) mL and (60.6 ± 0.9) × 106/mL, respectively. No significant decline in sperm counts was observed in any year during the entire study period. Only 1.8 % of the total number of sperm counts in the random sampling were less then 20 × 106/mL. On the basis of WHO criteria on motility, the total percentage of non-progressive and non-motile sperm in the ejaculate was higher (63 %)     

Body mass index has no impact on sperm quality but on reproductive hormones levels

The influence of overweight and obesity on sperm quality and reproductive hormone levels is under discussion. The aim of the present retrospective study was to evaluate the influence of body mass index (BMI) on sperm quality and reproductive hormones. We analysed semen samples and serum levels of FSH, LH, T and PRL of a total of 2110 men attending our andrology unit from 1994 to 2010 due to infertility work‐up. Patients were stratified according to their BMI in four groups. Main outcome measures were sperm motility, morphology and concentration. Serum levels of FSH, LH, T and PRL were evaluated as well. No statistically significant difference was found for sperm quality and BMI between patients categorised according to the four BMI levels. T (P < 0.001) and LH (P = 0.006) significantly differed between the four groups. In multivariable analysis, BMI did not have significantly independent influence on all assessed sperm quality parameters, whereas BMI significantly influenced hormone values for LH (P = 0.001), T (P = <0.001) and PRL (P = 0.044). We therefore conclude that BMI has no significant impact on sperm quality parameters. However, serum levels of LH, T and PRL were significantly influenced by BMI.     

Sperm DNA damage and its clinical relevance in assessing reproductive outcome

The routine examination of semen, which assesses sperm concentration, percentage motility and morphology,does not identify subtle defects in sperm chromatin architecture. The focus on the genomic integrity of the male gamete has intensified recently due to the growing concern that genetic diseases may be transmitted via assisted reproductive techniques (ART). Accordingly, the intent of this review is to describe the details of the informationpertaining to mitochondfial/nuclear sperm DNA damage with an emphasis on its clinical significance and its relationship with male infertility. Assessment of sperm DNA damage appears to be a potential tool for evaluating semen samples prior to their use in ART. Testing DNA integrity may help select spermatozoa with intact DNA or with the least amount of DNA damage for use in assisted conception. In turn, this may alleviate the financial, social and emotional problems associated with failed ART attempts.     

男性不育患者精子形态学分析与生殖激素关系的研究

目的:研究男性不育患者精子形态与生殖激素的关系,探讨畸形精子症的发病机制。方法:研究对象为90例男性不育患者,年龄25～40岁,利用Prader睾丸计评估患者睾丸容积,根据世界卫生标准进行精液常规分析,利用化学发光法测定血清生殖激素和性激素结合球蛋白(SHBG)浓度,计算得出游离睾酮和生物活性睾酮的浓度。结果:90例男性不育患者精子浓度均在正常范围,根据精子形态分析结果分为3个研究组,即组1(正常形态精子<4%)、组2(正常形态精子≥4%且<10%)和组3(正常形态精子≥10%),每组30例。3组之间年龄没有统计学差异(P>0.05);左侧睾丸容积分别为(14.27±3.65)ml,(16.90±3.57)ml和(14.57±3.57)ml,P组1,2=0.006,P组1,3=0.741和P组2,3=0.014;右侧睾丸容积分别为(14.60±3.70)ml,(16.60±3.35)ml和(14.67±3.54)ml,P=0.05;血清泌乳素(PRL)、卵泡刺激素(FSH)、黄体生成素(LH)、雌二醇(E2)、总睾酮(TT)和SH-BG在3组之间均没有统计学差异(P>0.05);血清游离睾酮(FT)水平分别为(0.25±0.07)nmol/L,(0.29±0.07)nmol/L和(0.31±0.13)nmol/L,P组1,2=0.086,P组1,3=0.010和P组2,3=0.364;生物活性睾酮(Bio-T)水平分别为(5.81±1.58)nmol/L,(6.78±1.55)nmol/L和(7.29±3.02)nmol/L,P组1,2=0.086,P组1,3=0.010和P组2,3=0.364。另外,正常形态精子百分率与血清FT、Bio-T水平之间均存在正相关(P<0.05)。结论:男性不育患者血清FT和Bio-T水平越高,则正常形态精子百分率越高,提示FT和Bio-T可能参与畸形精子症发病过程。     

不育男性精子染色质结构与精液常规参数的关系

目的 研究不育男性精子染色质结构参数与精液常规参数的关系.方法 采集36例男性不育患者和18例健康对照者的精液标本,用TUNEL法检测精子DNA碎片化,CMA3染色法检测精子染色质包装质量,按照世界卫生组织标准(1999)检测精液常规参数.结果 不育组的精子TUNEL阳性率和CMA3阳性率均显著高于健康对照组,差异具有统计学意义(P＜0.05),精液常规参数正常的不育男性精子TUNEL阳性率和CMA3阳性率也显著高于健康对照组,差异具有统计学意义(P＜0.05),精子TUNEL阳性率和CMA3阳性率与精液常规参数之间具有显著的相关性(P＜0.05).结论 不育男性的精子染色质结构检测结果与健康男性存在显著差异,精子染色质结构检测可提供反映男性生育能力的信息.     

Obesity leads to higher risk of sperm DNA damage in infertile patients

There has been a growing interest over the past few years in the impact of male nutrition on fertility. Infertility has been linked to male overweight or obesity, and conventional semen parameter values seem to be altered in case of high body mass index （BMI）. A few studies assessing the impact of BMI on sperm DNA integrity have been published, but they did not lead to a strong consensus. Our objective was to explore further the relationship between sperm DNA integrity and BMI, through a 3-year multicentre study. Three hundred and thirty male partners in subfertile couples were included. Using the terminal uridine nick-end labelling （TUNEL） assay, we observed an increased rate of sDerm DNA damage in obese men （odds ratio （95% confidence interval）： 2.5 （1.2-5.1））.