男性性腺功能低减的雄激素替代治疗

男性性腺功能低减在男科临床常见 ,分为原发性和继发性两类 ,共同之处都在于雄激素不足。除病因治疗外 ,所有原发性性腺功能低减和没有生育力要求的继发性性腺功能低减病人都应采用雄激素替代治疗。目前可应用和正在研究中的雄激素制剂很多 ,应合理选择使用     

雄激素对男性性腺功能低减病人促红细胞生成素的影响

目的 :观察雄激素替代治疗对性腺功能低减男子促红细胞生成素 (EPO)的影响 ,探讨雄激素促进红细胞和血红蛋白生成增加的机制。　方法 :8例原发性性腺功能低减 (Klinefelter综合征 )病人 ,接受初次 5 0 0mg或10 0 0mg十一酸睾酮 (TU)肌肉注射 ,间隔 3个月后交叉剂量第二次注射。注射前后观察血清性激素水平的变化 (放免法 ) ;在注射前和后的第 4、8周分别查血常规和红细胞比容 ,酶免疫法测定血清EPO。　结果 :注射TU后 ,第二性征发育情况改善 ,血睾酮水平显著升高 ,注射后 1周达峰值 ,维持有效治疗的雄激素水平 (>10nmol/L)超过 6周。血红细胞计数、红细胞比容和血红蛋白含量的均数均有不同程度的增加趋势 ,但统计学上差异不显著 (P >0 .0 5 )。与治疗前相比 ,注射TU后EPO水平显著升高 ,并维持 8周以上 (P <0 .0 1～ 0 .0 5 ) ;第 2次注射TU仍然使EPO水平升高。　结论 :雄激素替代治疗使性腺功能低减男子EPO水平升高 ,是红细胞生成增加的机制之一。     

男性特发性低促性腺激素型性腺功能减退症的诊治分析

目的 探讨男性特发性低促性腺激素型性腺功能减退症( idiopathic hypogonadotropic hypogonadism,IHH)的临床特点及诊治效果. 方法 回顾性分析2004年12月至2010年8月收治男性IHH患者92例资料,患者年龄(21.0±3.2)岁.伴有嗅觉减退或缺失(卡尔曼综合征,KS)52例,表现为部分青春期发育47例,无明显青春期发育45例,男性乳腺发育3例,单侧隐睾15例,双侧隐睾5例.92例染色体核型均为46,XY.血清甲状腺、肾上腺功能及糖脂代谢检测正常;92例患者血清黄体生成素(0.7±0.3)U/L,卵泡刺激素(0.8±0.4)U/L,睾酮(0.8±0.1)nmol/L,均低于正常值;6例行骨龄测定5例落后于实际年龄1～5年;头颅MRI检查显示52例KS患者均存在嗅球或嗅沟缺失或发育不良;92例患者均无下丘脑-垂体区占位性器质性病变.分别行绒毛膜促性腺激素(HCG,2000 U肌内注射,1周2次)加或不加雄激素(十一酸睾酮40 mg口服,2次/d)替代疗法,疗程1～5年,每3～6个月随访1次. 结果 92例治疗后均有明显的第二性征发育,性功能改善,治疗后血清睾酮水平为(11.0±0.8)nmol/L,与治疗前比较差异有统计学意义(P＜0.05).3例结婚,性功能评价正常,1例生育. 结论 根据第二性征发育异常患者合并的各种先天异常、病史、体格检查、染色体核型分析、性激素水平、MRI等可进行IHH的诊断与鉴别诊断,雄激素与HCG替代疗法是治疗该病的有效方法.     

性腺功能减退者接受前列腺癌根治术后的雄激素替代治疗

作者报道7例患局限性前列腺癌的性腺机能减退患者，在接受治愈性前列腺根治切除后给予睾酮替代治疗。同时应用MEDLINE和BIOSIS浏览器检索了对前列腺癌患者手术治愈后给予睾酮治疗的相关文献。7例患者均有性腺机能低下的症状，血清睾酮水平低于正常。结果显示，分别给予雄激素制品治疗后．在不同随访时间中均未发现肿瘤的生化及临床复发征象；     

特发性低促性腺激素性性腺功能减退症的药物治疗

特发性低促性腺性性腺功能减退症(IHH)是一种相对少见疾病,但却可以有效治疗。多数患者因青春期启动异常或缺乏、男性第二性征发育不良或不育而就诊,并存在性腺激素缺乏的系列症状。治疗目的是维持男性第二性征的正常发育和恢复生育能力,药物治疗主要以激素替代为主,绝大多数患者的预后良好,可以获得满意的男性第二性征发育、恢复睾丸的生精能力,甚至可以达到自然妊娠的目的。     

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。     

男性性腺功能低减病人尿β-FSH排泄连续测定

目的 :连续观察男性性腺功能低减病人尿卵泡刺激素 β亚单位 (β FSH)的排泄 ,探讨其对男性性腺功能低减的临床分类诊断和病理生理机制研究的意义。　方法 :4例健康成年男性 (年龄分别为 19、2 2、2 7、33岁 )、4例低促性腺激素型性腺功能低减男性病人 (年龄分别为 17、17、19、2 4岁 )和 5例高促性腺激素型性腺功能低减男性病人 (年龄分别为 16、16、17、2 0、2 2岁 ) ,连续留晨尿 30～ 32d ,其中 1例正常男性留取标本 6 3d。酶免法测定尿 β FSH ,以肌酐 (Cr)含量进行校正。　结果 :4例正常成年男性尿 β FSH总平均为 (1.16± 0 .2 0 ) μg/mgCr,均可出现波峰 ,最大峰值为 2 .76 μg/mgCr。 4例低促性腺激素型性腺功能低减男性病人 [Kallmann或特发性低促性腺激素型性腺功能低减 (IHH) ]尿 β FSH分别为 (0 .5 8± 0 .31)、(0 .93± 0 .4 7)、(0 .4 7± 0 .33)、(0 .6 0± 0 .4 0 ) μg/mgCr,曲线上未见明显波动。 5例高促性腺激素型性腺功能低减男性病人 (Klinefelter)尿 β FSH分别为 (3.0 2± 0 .93)、(4.36± 1.12 )、(4.79± 0 .78)、(4.6 4± 1.4 2 )、(3.88± 1.4 2 ) μg/mgCr,曲线上出现显著不规则波动 ,最大峰值达6 .83μg/mgCr。所有病人第二性征发育差 ,血清T水平显著低下。低促性腺激素?     

胎儿睾丸移植在男性性腺功能减退症治疗中的应用

目的 :探讨胎儿睾丸移植在男性性腺功能减退症治疗中的临床应用价值。　方法 :利用胎儿睾丸作供体 ,为 6例男性性腺功能减退症病人施行了胎儿睾丸移植术。　结果 :术后 5个月 ,6例病人的血清睾酮水平明显升高 ,性欲、性功能及第二性征明显改善 ,移植睾丸体积较术前增大。　结论 :胎儿睾丸移植治疗男性性腺功能减退症是有效的 ,且胎儿睾丸免疫原性低 ,具有较高的临床应用价值     

特发性低促性腺激素性性腺功能减退症不同治疗方案的研究进展

特发性低促性腺激素性性腺功能减退症(IHH)是临床上逐渐被认识的发育异常疾病,随着医学的不断发展,其治疗方法也逐渐趋于规范.对于IHH的治疗,男性的目前治疗方案主要包括睾酮替代、促性腺激素治疗和GnRH脉冲治疗.这三种方案可根据患者年龄、生活状态和需求进行选择,并可互相切换.女性在无生育需求时,予周期性雌、孕激素联合替...     

选择性雄激素受体调节剂治疗迟发性男性性腺功能低下症

几种睾酮制剂用于治疗老年男性性腺功能减退。这些疗法在其便利性、灵活性、区域供应和费用等方面有区别,但有共同的药代动力学基础,同时缺乏长期安全性数据。简洁和成本较低的基于药代动力学的注册临床试验使得开发改善性的治疗迟发性性腺功能减退的新疗法的商业动机减少了。在前列腺、头发、皮肤受雄激素缺乏影响的患者中,选择性雄激素受体调节剂已被证明可以提供合成代谢的好处。（目前,选择性雄激素受体调节剂的临床进展集中在有限定身体功能的临床终点的急性肌肉萎缩和低体重）。在具有有益的药理、理想的药代动力学的选择性雄激素受体调节剂应用于治疗迟发性男性性腺功能低下症前,其在男性性腺功能低下治疗中关于临床缺陷的更清晰的监管是必须的。     

The effect of androgen deprivation therapy on fasting serum lipid and glucose parameters

PURPOSE: Although prostate cancer specific mortality is decreasing, there is little effect on overall mortality in this population, suggesting the possibility of an increased risk of death from nonprostate cancer related causes. Androgen deprivation therapy could adversely affect cardiovascular health. We investigated changes in lipid and glucose during androgen deprivation therapy. MATERIALS AND METHODS: We performed an exploratory analysis of pooled data from 3 prospective clinical trials aimed at achieving medical castration by comparing the gonadotropin releasing hormone antagonist abarelix, the gonadotropin releasing hormone agonist leuprolide acetate and leuprolide acetate plus the antiandrogen bicalutamide. Most patients were treated in the neoadjuvant setting or because of biochemical recurrence. Fasting serum lipid, glucose and hemoglobin A1C were determined in 1,102 men at baseline, and on treatment days 85 and 169. In the current study men were categorized into 3 treatment groups according to the type of androgen deprivation therapy, that is leuprolide acetate, leuprolide acetate plus bicalutamide or abarelix, and statin therapy. RESULTS: Significant increases in total cholesterol, triglyceride and high density lipoprotein-cholesterol were observed in patients on leuprolide acetate or abarelix but not in patients on leuprolide acetate plus bicalutamide. Consistent changes in low density lipoprotein-cholesterol were not detected. Increased total cholesterol was usually due to an increase in high density lipoprotein-cholesterol. Hemoglobin A1C increased from baseline to day 85 only and there were no significant changes in fasting glucose measurements. The type of androgen deprivation therapy did not affect these parameters. CONCLUSIONS: Short-term androgen deprivation therapy affects serum lipid and hemoglobin A1C independent of statin therapy.     

Outcomes of clomiphene citrate treatment in young hypogonadal men

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Hypogonadism is a prevalent problem, increasing in frequency as men age. It is most commonly treated by testosterone supplementation therapy but in younger patients this can lead to testicular atrophy with subsequent exogenous testosterone dependency and may impair spermatogenesis. Clomiphene citrate (CC) may be used as an alternative treatment in these patients with hypogonadism when maintenance of fertility is desired. This study shows that CC is a safe and efficacious drug to use as an alternative to exogenous testosterone. Not only have we validated previous findings of other papers but have proven our findings over a much longer period (mean duration of treatment 19 months). This prospective study is the largest to date assessing both the objective hormone response to CC therapy as well as the subjective response based on a validated questionnaire.

OBJECTIVE

• ? To prospectively assess the andrological outcomes of long‐term clomiphene citrate (CC) treatment in hypogonadal men.

PATIENTS AND METHODS

• ? We prospectively evaluated 86 men with hypogonadism (HG) as confirmed by two consecutive early morning testosterone measurements <300 ng/dL.
• ? The cohort included all men with HG presenting to our clinic between 2002 and 2006 who, after an informed discussion, elected to have CC therapy. CC was commenced at 25 mg every other day and titrated to 50 mg every other day. The target testosterone level was 550 ± 50 ng/dL.
• ? Testosterone (free and total), sex hormone binding globulin, oestradiol, luteinizing hormone and follicle stimulating hormone were measured at baseline and during treatment on all patients. Once the desired testosterone level was achieved, testosterone/gonadotropin levels were measured twice per year.
• ? To assess subjective response to treatment, the androgen deficiency in aging males (ADAM) questionnaire was administered before treatment and during follow‐up.

RESULTS

• ? Patients' mean (standard deviation [sd ]; range) age was 29 (3; 22–37) years. Infertility was the most common reason (64%) for seeking treatment. The mean (sd ) duration of CC treatment was 19 (14) months.
• ? At the last evaluation, 70% of men were using 25 mg CC every other day, and the remainder were using 50 mg every other day.
• ? All mean testosterone and gonadotropin measurements significantly increased during treatment.
• ? Subjectively, there was an improvement in all questions (except loss of height) on the ADAM questionnaire. More than half the patients had an improvement in at least three symptoms.
• ? There were no major side effects recorded and the presence of a varicocele did not have an impact on the response to CC.

CONCLUSION

• ? Long‐term follow‐up of CC treatment for HG shows that it appears to be an effective and safe alternative to testosterone supplementation in men wishing to preserve their fertility.

     

Metabolic and cardiovascular effects of androgen deprivation therapy

Prostate cancer is the most common gender-specific malignancy in men in the USA. Androgen-deprivation therapy (ADT) is commonly used in the treatment of metastatic or recurrent prostate cancer. The use of ADT is increasing with the advocacy of adjuvant and neoadjuvant ADT for treating asymptomatic patients with locally advanced prostate cancer. Although the use of ADT has resulted in improved survival in men with advanced prostate cancer, ADT, with its resulting severe hypogonadism, causes profound metabolic side-effects. We comprehensively reviewed previous reports using Medline searches of English-language literature (1950 to the present), with the keywords 'hypogonadism', 'testosterone', 'androgen deprivation therapy', 'hormonal treatment', 'prostate cancer', 'diabetes', 'metabolic syndrome', and 'cardiovascular disease'. Men with prostate cancer who undergo long-term ADT are at greater risk of developing dyslipidaemia, insulin resistance, hyperglycaemia and metabolic syndrome. These metabolic and physiological changes are a direct result of the induced severe hypogonadism and might predispose patients to a greater risk of cardiovascular morbidity and mortality. There is a need for prospective studies aimed and designed to investigate the metabolic and cardiovascular adverse effects of ADT, and assess the benefit/risk ratio, especially in special populations such as diabetics.     

Responses of serum testosterone levels to human chorionic gonadotrophin stimulation in patients with Klinefelter''s syndrome after long-term androgen replacement therapy

Responses of serum testosterone levels to repeated daily injections of 5000 IU hCG for 4 days were studied in 24 patients with Klinefelter's syndrome. Eighteen patients were untreated, and 8 had been given previous treatment with depot testosterone 100 mg intramuscularly every 2-3 weeks for an average duration of 4.7 years. Among them, 4 patients were examined both before and after the therapy. The hCG test was performed at least 2 weeks (0.5-12 months) after the last injection of depot testosterone in the treated patients. Mean basal testosterone level of the treated patients, 139 +/- 98 ng/dl (Mean +/- SD), was not significantly different from that of the untreated patients, 172 +/- 110 ng/dl. Maximum stimulated testosterone level in the treated patients, 170 +/- 107 ng/dl (P less than 0.05). These results suggest that long-term androgen administration may decrease the functional reserve of Leydig cells in patients with Klinefelter's syndrome.     

Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy

OBJECTIVE

To analyse individual variations in serum testosterone level, the cumulative rate of ‘breakthrough’ increases over castrate levels, and to evaluate whether the increases can be predicted.

PATIENTS AND METHODS

Serum testosterone levels were determined every 6 months over 3 years in 73 consecutive patients with prostate cancer who were medically castrated, prospectively enrolled in a single tertiary academic centre. Patients recruited for this study were being treated with a 3‐monthly depot of luteinizing hormone‐releasing hormone agonist over 6–48 months. Serum testosterone was measured using a chemiluminescent assay with a lower sensitivity level of 15 ng/dL and interassay coefficient of variation of 25% at low testosterone concentrations.

RESULTS

Individual variations could not be explained by the interassay variation coefficient in 26% of the patients. The rate of breakthrough increases >50 ng/dL increased from 12.3% at the first determination to 24.7% at the third, then remaining stable. The rate of breakthrough increases of 20–50 ng/dL increased from 27.4% at the first determination to 31.5% at the second, and then remained stable. A first determination of <20 ng/dL provided an 11.4% probability for future increases of >50 ng/dL, with a 5.7% probability if two consecutive determinations were <20 ng/dL and a null probability when three consecutive determinations were <20 ng/dL.

CONCLUSIONS

Individual variations in serum testosterone level cannot be explained by the coefficient of variation of the assay in a quarter of patients who are medically castrated. Breakthrough increases over castrate levels increase over time and those of >50 ng/dL can be predicted from the previous levels.     

Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications

Prostate cancer (PCa) is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.     

The effect of therapy on the concentration and occupancy of androgen receptors in human prostatic cytosol

With a protamine sulphate precipitation method, total and free cytosol AR was assayed in BPH and prostatic carcinoma tissue, in order to investigate possible differences in AR concentration that might relate to the histo-pathology of the tissue or to endocrine manipulation of the patients. Similar ranges of total cytosol AR concentrations were observed in BPH and untreated prostatic carcinoma, but the latter tended to have a higher proportion of apparently free sites. Moreover, the proportion of "free" sites in the untreated carcinoma tissue appeared to be related to the proportion of poorly differentiated carcinoma in the specimen. In patients whose endogenous androgen levels had been lowered by treatment, the proportion of free sites tended to be higher, but a considerable proportion of sites appeared to be still occupied. Carcinoma tissue from some estrogen-treated patients had high cytosol AR concentrations. It is suggested that, in some treated patients, androgens of adrenal origin may occupy some AR sites and that some carcinomas may contain a considerable concentration of nonfunctional AR.     

Prostate‐specific antigen changes and prostate cancer in hypogonadal men treated with testosterone replacement therapy

OBJECTIVES

To retrospectively review hypogonadal men receiving testosterone replacement therapy (TRT), and evaluate the changes in prostate‐specific antigen (PSA) levels over an extended period, and thus evaluate the occurrence of prostate cancer, as a primary concern in treating late‐onset hypogonadism (LOH) is the potential increased risk of prostate cancer; we also recorded the cardiovascular effects of TRT.

PATIENTS AND METHODS

In all, 81 hypogonadal men (mean age 56.8 years) were followed for a mean (range) of 33.8 (6–144) months after starting TRT. All men had a normal baseline PSA level before TRT and had routine laboratory investigations, including measurements of body mass index (BMI), haematocrit, lipid profile, and liver function tests (LFTs). Testosterone and PSA levels were assessed every 6–12 months. Patients with a biopsy‐confirmed or recent history of prostatitis before treatment were excluded. TRT was discontinued in men who developed prostate cancer.

RESULTS

Before and 36 months after treatment the total testosterone levels were 241.1 and 379.8 ng/dL (P < 0.05), respectively. Four men (4.9%) developed prostate cancer at a mean (range) of 32.5 (22–41) months after starting TRT. In men without prostate cancer (95.1%), PSA levels did not increase significantly at 1‐year intervals for 5 years. There was no statistical difference in PSA level change from baseline to 36 months when patients without prostate cancer were stratified into groups according to age (≤50, 55–65 and ≥70 years). In men with prostate cancer there was an increase in mean PSA level from baseline to 18 months of 1.8 ng/mL, and to 36 months of 3.2 ng/mL (P < 0.05). Total cholesterol improved from 203.8 to 166.6 mg/dL (P < 0.05) after 36 months of TRT; the BMI, haematocrit and LFTs did not change significantly.

CONCLUSIONS

LOH is an increasingly prevalent disease characterized by a symptomatically low testosterone level, and TRT is effective in normalizing serum testosterone levels, providing a beneficial cardiovascular effect, and improving sexual function and overall quality of life. PSA levels remain stable after normalization of testosterone for ≥5 years, prostate cancer can be effectively diagnosed and treated in men taking TRT, and the incidence of prostate cancer among men with LOH on TRT is no greater than that in the general population.