ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males

The new ISA, ISSAM, EAU, EAA and ASA recommendations on the investigation, treatment and monitoring of late-onset hypogonadism in males provide updated evidence-based information for clinicians who diagnose and treat patients with adult onset, age related testosterone deficiency.     

雄激素受体基因CAG多态性与迟发性性腺功能减退症的相关性研究

目的:研究雄激素受体基因(AR)重复序列(CAG)n多态性与迟发性性腺功能减退症(LOH)的关系,探讨LOH的发病机制。方法:共调查1 000例40～70岁中老年男性,其中19例迟发性性腺功能减退症患者,随机抽取127例正常健康中老年男性,测定甘油三酯(TG)、空腹血糖(FBG)、血清总睾酮(TT)、游离睾酮(fT),测量身高、体重、腰围(WC)、血压,并采用DNA测序方法进行AR基因外显子1氨基端转录调节区(CAG)n重复序列长度测定,比较两组各指标之间的差异。结果:(CAG)n重复次数为15～32(23.05±2.95)。正常健康中老年男性的体重指数(BMI)、FBG较LOH患者显著下降(P<0.01),而TG、TT及fT较LOH患者显著升高(P<0.01)。正常健康中老年男性AR基因(CAG)n重复数为22.54±3.06;LOH患者AR基因(CAG)n重复数为23.23±2.24;LOH患者(CAG)n重复数略高于正常健康人群,但两者比较无统计学意义(P=0.946)。(CAG)n重复长度显示:长组(n≥22)AR基因(CAG)n在LOH组和正常健康中老年男性组的频率分别为73.68%和48.82%(P<0.05)。相关分析显示:TT、fT与(CAG)n重复序列无明显相关性(r=0.04和r=0.025,P>0.05)。结论:LOH男性AR基因(CAG)n重复序列呈现多态性,长(CAG)n重复多态可能是LOH发病的遗传因素,但仍需进一步扩大样本量证实。     

Survey for late-onset hypogonadism among old and middle-aged males in Shanghai communities

This study sought to investigate late-onset hypogonadism (LOH) in old and middle-aged males in Shanghai communities, using symptom score evaluation systems and measurements of sex hormone levels. One thousand cases of males aged 40-70 years were investigated. The aging male symptoms (AMS) scale and androgen deficiency in aging males (ADAM) questionnaire were used at the beginning of the investigation, followed by measurement of the sex hormone-related factors (total testosterone (TT), free testosterone (fT), sex hormone-binding globulin (SHBG) and bioavailability of testosterone (Bio-T)). There were 977 valid questionnaires. The LOH-positive rates shown by AMS and ADAM were 59.88% and 84.65%, respectively; values increased with the age of the patients. There were 946 results related to sex hormone measurements, which showed the following results: TT was not related to aging (P>0.05); levels of SHBG increased with age; and fT and Bio-T decreased with age. There was a significant difference in fT between LOH-positive and LOH-negative patients, as shown by the ADAM. In summary, TT levels were not related to aging, even though SHBG did increase while fT and Bio-T decreased with aging. Clinically, the diagnosis of LOH cannot be based on serum TT level.     

他达拉非对中老年男性LOH患者T、IIEF及SEP影响的临床研究

目的:观察他达拉非联合安特尔治疗中老年男性迟发性性腺功能低下(LOH)的临床疗效。方法:选择125例中老年男性LOH患者随机分为两组,治疗组65例使用他达拉非加十一酸睾酮治疗,对照组60例使用十一酸睾酮胶囊治疗。分别记录治疗前及治疗后4周时的总睾酮(T)、国际勃起功能指数评分(IIEF)、患者性生活日记(SEP)等的变化。结果:治疗后2组T、IIEF及SEP评分均有不同程度改善,与治疗前比较,差异均有统计学意义(P<0.05);治疗组T、IIEF及SEP评分改善更为显著,与对照组比较,差异均有统计学意义(P<0.05)。结论:使用他达拉非联合十一酸睾酮胶囊,可较好地改善中老年男性患者T、IIEF及SEP分数,提高患者性生活满意度及自信心,具有比单纯补充睾酮更好的综合疗效。     

Prevalence of late-onset hypogonadism among middle-aged and elderly males in China:results from a national survey

This study aimed to propose an operational definition of late-onset hypogonadism(LOH)that incorporates both clinical symptoms and serum testosterone measurements to evaluate the prevalence of LOH in aging males in China.A population-based sample of 6296 men aged 40 years-79 years old was enrolled from six representative provinces in China.Serum total testosterone(TT),sex hormone-binding globulin(SHBG),and luteinizing hormone(LH)were measured and free testosterone(cFT)was calculated.The Aging Males’Symptoms(AMS)scale was used to evaluate the LOH symptoms.Finally,5078 men were included in this analysis.The TT levels did not decrease with age(P=0.59),and had no relationship with AMS symptoms(P=0.87 for AMS total score,P=0.74 for≥3 sexual symptoms).The cFT levels decreased significantly with age(P<0.01)and showed a negative association with the presence of≥3 sexual symptoms(P=0.03).The overall estimated prevalence of LOH was 7.8%(395/5078)if a cFT level<210 pmol l?1 combined with the presence of≥3 sexual symptoms was used as the criterion of LOH.Among them,26.1%(103/395)and 73.9%(292/395)had primary and secondary hypogonadism,respectively.After adjustment for confounding factors,primary and secondary hypogonadism was positively related to age and comorbidities.Body mass index was an independent risk factor for secondary hypogonadism.The results suggest that the AMS total score is not an appropriate indicator for decreased testosterone,and that the cFT level is more reliable than TT for LOH diagnosis.Secondary hypogonadism is the most common form of LOH.     

佳蓉片联合十一酸睾酮胶丸治疗迟发性性腺功能减退症的多中心临床疗效观察

目的:评价佳蓉片联合十一酸睾酮胶丸治疗男性迟发性性腺功能减退(LOH)的安全性和有效性。方法:采用随机、开放、多中心的临床研究方法,选取200例符合纳入标准的LOH患者,按照数字表法随机分为试验组和对照组各100例,对照组给予患者口服十一酸睾酮胶丸,40 mg/次,2次/d;试验组在此基础上加用佳蓉片,4片/次,3次/d,两组均连续服用12周。分别记录基线期及治疗后两组患者AMS评分、IIEF-5评分、血清TT以及安全性指标(红细胞计数、肝功能、肾功能、血糖以及总前列腺特异性抗原)。结果:191例符合纳入标准的LOH患者完成试验,以AMS评分、血清TT以及IIEF-5评分作为疗效评价指标,经过3个月治疗后,试验组在AMS评分(20.6±5.7)、血清TT(16.1±3.9) nmol/L以及IIEF-5评分(20.3±3.1)方面均优于对照组(31.9±6.1)、(12.7±3.4) nmol/L、(16.3±3.8),差异具有统计学意义(P<0.05)。两组患者治疗前后红细胞计数、肝功能、肾功能、血糖以及tPSA均未发现异常,也无明显的不良反应事件。结论:佳蓉片联合十一酸睾酮胶丸治疗LOH优于单一使用十一酸睾酮胶丸,安全有效,值得临床推广应用。     

十一酸睾酮治疗LOH的疗效与安全性的Meta分析

目的:应用Meta分析的方法评价十一酸睾酮治疗迟发性性腺功能减退(LOH)的疗效及安全性。方法:计算机检索Pubmed(至2014年4月1日)、Embase(至2014年3月28日)、Cochrane library(至2014年4月17日)、中国生物医学文献数据库(2001年1月1日至2014年2月2日)、中国期刊全文数据库(2001年1年1至2014年2月2日)、万方数据库(2000年1月1日到至2014年2月2日)、维普数据库(2000年1月1至2014年2月2日)。检索已经阅读的文献的参考文献。纳入十一酸睾酮(TU)治疗LOH的随机对照试验。采用Rveman5.2软件对纳入的文献进行质量评价及Meta分析。结果:筛选后纳入文献14篇,共1686例患者,Meta分析显示:与安慰剂或空白对照组相比,经十一酸睾酮治疗后的血清总睾酮升高[SMD=6.22,95%CI(3.99,8.45),P0.01];血清游离睾酮升高[SMD=4.35,95%CI(1.86,6.85),P0.01];黄体生成素下降[WMD=-2.23,95%CI(-4.03,-0.42),P0.01];性激素结合球蛋白下降[WMD=2.00,95%CI(1.38,2.63),P0.05];PADAM症状量表评分降低[WMD=-9.29,95%CI(-12.96,-6.03),P0.01];AMS症状量表评分降低[WMD=-2.76,95%CI(-4.85,-0.66),P0.05],血红蛋白升高[SMD=2.35,95%CI(0.29,4.41),P0.05],血细胞压积升高[SMD=4.35,95%CI(1.36,7.33),P0.01];谷草转氨酶、谷丙转氨酶、前列腺特异抗原、前列腺体积等无显著性差异(P均0.05)。结论:十一酸睾酮能显著改善LOH患者的血清雄激素水平及临床症状,且未发现严重的不良反应;但由于纳入的研究数量较少,质量偏低,上述结论应用于临床需谨慎。     

The characteristics of late-onset hypogonadism, its prevalence, symptoms, and diagnosis

With aging in most but not all men

• Total testosterone levels decline

• Even more so free testosterone levels

• This is associated with symptoms of testosterone deficiency, not only of sexual functioning but also of bone density, muscle mass and metabolic risk factor for cardiovascular disease and diabetes

• The diagnosis is based both on clinical symptoms and on laboratory measurements, more so of free testosterone than of total testosterone.

• Treatment with testosterone is acceptably safe provided established guidelines are adhered to

益肾活血法对肾虚型LOH患者睾酮分泌指数的影响

目的:探讨中医益肾活血法对肾虚型迟发性性腺功能减退症(LOH)患者睾酮分泌指数的影响及治疗机制。方法:采用中国中老年男子健康研究会(CHISAM)认可的《男性更年期自我评定表》进行症状评分,检测血清总睾酮(TT)、黄体生成素(LH)的水平,并依据TT/LH计算出TSI(睾酮分泌指数)值,筛选出60例肾虚型LOH患者入组,按2∶1随机分为中药组和对照组。中药组用男更宁汤剂治疗;对照组用十一酸睾酮口服治疗,疗程均为12周。观察治疗后第4、8、12周两组患者心理学分量表评分、躯体分量表评分、性分量表评分、TT、LH和TSI的变化。结果:①中药组与对照组治疗前LH的水平分别为(5.32±2.08)、(5.36±2.07)IU/L,治疗12周后为(4.89±1.46)、(4.81±1.75)IU/L,两组治疗前后差异具有显著性(P均<0.05);两组治疗前心理学分量表评分分别为(5.2±1.3)、(4.8±2.2)分,治疗12周后分别为(2.7±1.4)、(2.9±1.2)分,两组治疗前后差异均具有显著性(P均<0.05);两组躯体分量表评分分别为(6.9±2.5)、(7.1±2.7)分,治疗12周后分别为(2.9±1.6)、(3.1±1.5)分,两组治疗前后差异具有显著性(P均<0.05);两组性分量表评分分别为(10.2±3.3)、(9.8±3.1)分,治疗12周分别为(4.5±2.9)、(4.8±3.0)分,两组治疗前后差异有显著性(P均<0.05);②两组治疗前TT分别为(11.13±0.69)、(10.99±0.74)nmol/L,治疗12周后分别为(14.55±0.75)、(14.74±0.83)nmol/L,差异有显著性(P均<0.05);两组治疗前TSI分别为(2.14±0.65)、(2.05±0.73)nmol/IU,治疗12周后分别为(2.99±0.72)、(3.11±0.65)nmol/IU,差异有显著性(P均<0.05);③中药组治疗12周后LH、TT、TSI、心理学分量表评分、躯体分量表评分、性分量表评分分别为(4.89±1.46)IU/L、(14.55±0.75)nmol/L、(2.99±0.72)nmol/IU、(2.7±1.4)分、(2.9±1.6)分、(4.5±2.9)分,对照组治疗12周后分别为(4.81±1.75)IU/L、(14.74±0.83)nmol/L、(3.11±0.65)nmol/IU、(2.9±1.2)分、(3.1±1.5)分、(4.8±3.0)分,两组间对比差异无显著性(P均>0.05)。④整个治疗过程,两组均无不良事件发生。结论:益肾活血法治疗肾虚型LOH可显著改善患者临床症状,同时使TT水平、TSI水平升高,疗效与补充雄激素治疗相当;男更宁汤通过下丘脑-垂体-性腺轴发挥作用可能是其治疗LOH的主要机制之一。     

Diagnosis and therapy of hypogonadism in adult males

Hypogonadism in men is defined as endocrine dysfunction of the testes, and due to reduced serum testosterone levels leads to symptoms of testosterone deficiency. Depending on the location of disruption in the endocrinological cycle, hypogonadism is classified as primary, secondary, or tertiary. In primary hypogonadism, the production of testosterone in the Leydig's cells of the testes does not function properly. Serum LH concentrations are elevated in the sense of counterregulation (hypogonadotropic hypogonadism). In secondary hypogonadism, LH secretion (and usually also FSH) from the hypophysis is impaired so that Leydig's cells are not stimulated, while in tertiary hypogonadism the hypothalamus is damaged. The clinical course in cases of reduced serum testosterone levels is determined essentially by the point in time when hypogonadism becomes manifest. Delayed puberty, eunuchoid stature, and underdeveloped secondary sex characteristics suggest prepubertal onset of hypogonadism.     

Association of hypogonadism symptoms and serum hormones in aging males

The association between hypogonadism symptoms and the levels of serum hormones are still in debate. To investigate the relationship between hypogonadism symptoms and serum hormones in middle-aged and elderly Chinese men, this community-based cross-sectional study was conducted based on a total of 965 ageing men. The ageing males’ symptom (AMS) scale, International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS) questionnaires and related variables were assessed. Blood tests for total testosterone (TT), sex hormone-binding globulin (SHBG) and luteinising hormone (LH) were performed. Serum level of free testosterone (FT) and bioavailable testosterone (Bio-T) was calculated. The mean age was 56.34 ± 8.85 years. Total AMS score was significantly associated with all five serum hormones (LH: p < 0.001; SHBG: p < 0.001; TT: p =.043; FT: p = 0.007; Bio-T: p < 0.001). We identified sexual and somatic symptoms were obviously related to five serum hormones, while psychological symptoms seemed to have no association with serum hormones. After adjusting for age and BMI, multiple linear regression analysis indicated that LH had positive correlations with total AMS score, somatic and sexual symptom score (p < 0.05). In conclusion, LH and SHBG had the strongest correlation hypogonadism and might be used as early predictors for symptomatic hypogonadism in the near future.     

Efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males with clinical varicocele: A meta‐analysis

To reassess the efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males, we carried out a meta‐analysis of clinical trials and retrospective studies that compared the pre‐operative and postoperative serum testosterone. We searched Embase and PubMed (1980 to May 2016) for studies. Eight studies and 712 patients were included. The combined analysis of seven studies discovered that the mean serum testosterone of patients post‐operation improved by 34.3 ng/dl (95% CI: 22.57–46.04, p < .00001, I² = 0.0%) compared with their pre‐operative levels. In subgroup analysis, testosterone improvements in the hypogonadal treated subgroup were more significant (improved by 123 ng/dl, 95% CI: 114.61–131.35, p < .00001, I² = 37%) than in the eugonadals, or the untreated controls. In an analysis of surgery versus untreated control (three studies included), results showed that mean testosterone among hypogonadals increased by 105.65 ng/dl (95% CI: 77.99–133.32), favouring varicocelectomy, as the differences were significant (p < .00001), However, there were insignificant differences in eugonadals (p = .36). In conclusion, varicocelectomy significantly improved testosterone in hypogonadal men with subfertility. Active surgical treatment of varicocele might have a benefit of maintaining healthy androgen levels in subfertile men.     

Efficiency of intracavernosal alprostadil and oral clomiphene citrate combination treatment in penile vasculogenic erectile dysfunction patients accompanied by late-onset hypogonadism

In this study, the efficiency of intracavernosal alprostadil + oral clomiphene citrate (CC) treatment in late-onset hypogonadism (LOH) accompanied by penile vasculogenic erectile dysfunction (PVED) in patients irresponsive to phosphodiesterase type 5 inhibitor treatment was evaluated. A total of 31 patients with concurrent PVED and LOH were included in the study. The patients were given intracavernosal alprostadil (10–20 μg) and oral CC (50 mg) every day for 12 weeks. Before and after treatment, a 15-question International Index of Erectile Function (IIEF-15) questionnaire, Erection Hardness Score (EHS), Sexual Encounter Profile (SEP)2 and SEP3 levels were analysed, and follicle stimulating hormone (FSH), luteinising hormone (LH), total testosterone and prostate-specific antigen (PSA) levels were measured. In all, 41.9% of patients had pure arterial deficiency, 19.3% had pure venous deficiency, and 38.7% had arterial + venous (mixed) deficiency. A significant increase was detected in total testosterone, FSH, LH and PSA values after treatment when compared to values before treatment (p < .001, p < .001, p < .001 and p = .034 respectively). A significant recovery was observed in IIEF-15 subscores, EHS and SEP2-SEP3 results. In PVED patients accompanied by LOH, intracavernosal alprostadil and oral CC combination is an efficient, low cost, safely applicable and tolerable treatment.