Androgen therapy in the aging male

The world population is expanding rapidly; at the same time, life expectancy is increasing, and fertility rates are decreasing. Due to these facts, it is expected that the biggest increases of population growth will occur in the aging population. In the aging male, endocrine changes and a decline in endocrine function involve tissue responsiveness as well as reduced secretory output from peripheral glands and alterations in the central mechanism controlling the temporal organization of hormonal release. The latter are likely to be responsible for the dampened circadian hormonal and non-hormonal rhythms. These are in part responsible for the age-dependent decrease of the peripheral levels of testosterone, dehydroepiandrosterone (DHEA), the thyroid hormones, growth hormone (GH), IGF1 and melatonin. These hormonal changes, which develop in most men at about the age of 50, are in part responsible for endocrine deficiencies of some older men. One of the best-studied endocrine deficiencies is late-onset hypogonadism. This is a syndrome characterized by adverse effects on multiple organ systems and decreased quality of life, associated with advancing age and characterized by signs and symptoms of hypogonadism and a deficiency in serum androgen levels with or without a decreased genomic sensitivity to androgens. In cases of endocrine deficiencies, traditional endocrinology aims to replace the missing hormone or hormones with substitutes. It has been demonstrated that interventions such as hormone therapies may favorably influence some of the pathological conditions in aging men by preventing the preventable and delaying the inevitable. A comprehensive medical, psycho-social and life-style history, a physical examination and laboratory testing are essential for the diagnosis and management of late-onset hypogonadism. Acute, chronic or inter-current diseases must be taken into consideration prior to initiating any hormonal substitution therapy. In the era of evidence-based medicine, we have to acknowledge that data on testosterone therapy (HT) in the aging male is mostly circumstantial, based on experience in the treatment of transitional or chronic hypogonadism in young men resulting from disease or experiments of nature. However, over the past several years prospective studies on testosterone therapy in the aging male were performed and shown to be beneficial for certain older men in preventing or delaying some aspects of aging. Recommendations for algorithms for the diagnosis of late-onset hypogonadism and monitoring therapy for safety and efficacy are the subject of this paper.     

中老年男性部分雄激素缺乏

男性随着年龄增长 ,雄激素水平逐渐下降 ,导致男性体力 ,性功能和各种代谢的变化 ,并对肌肉、骨骼、脂肪代谢以及认知能力产生不良影响。雄激素补充治疗可以改善这些症状     

Androgen deficiency impairs erectile function in rats through promotion of corporal fibrosis

The aim of this study was to investigate the underlying mechanism of androgen deficiency inducing corporal fibrosis, thereby causing erectile dysfunction (ED). Forty 12‐week‐old healthy male rats were divided randomly into four groups: normal control group (Control); castration group (Castration); the other 20 rats were castrated followed by testosterone (T) (orally) each day: castration + 10mg/kg T group (Castration + 10T) and castration + 20 mg/kg T group (Castration + 20T). After 8 weeks' treatment, the main outcome measures were the following: serum levels of T; the ratios of intracavernous pressure (ICP) to mean arterial pressure (MAP); histologic changes in penile smooth muscle cells; the Smad and non‐Smad pathways; and extracellular matrix (ECM) protein deposition. Castration group showed lower level of T and ratio of ICP/MAP, reduced ratio of penile smooth muscle cells/collagen, increased extracellular matrix protein deposition, and a higher expression of the Smad and non‐Smad pathways. Castration + 10T partially preserved erectile function and histology stabilisation. However, the Castration + 20T group showed significantly better erectile function and molecular changes. Better efficacy could be expected with ART of adequate dose. Androgen deficiency induces corporal fibrosis through activation of the Smad and non‐Smad pathways, and accumulation of ECM proteins.     

Androgen deprivation therapy: a primer on concepts and therapeutic options

Prostate cancer is a cause of significant morbidity and mortality in men. Endogenous levels of androgen, produced by the testis and adrenal gland, have a complex and controversial role in the development and progression of prostate cancer. Androgen deprivation therapy (ADT) is a common treatment for prostate cancer, particularly in metastatic tumor cases and in certain cases of locally advanced disease. This paper reviews the surgical and medical options used to produce androgen blockade. Bilateral orchiectomy is the historic gold standard with fewer side effects than medical castration, although currently less frequently utilized. Gonadotropin releasing hormone (GnRH) agonists are the most commonly used medications for achieving castration. Other medications include estrogens, GnRH antagonists, steroidal and non-steroidal anti-androgens and 5-alpha reductase inhibitors. The advantages and side effects of each type of medication are described. Intermittent therapy and continuous androgen deprivation is discussed. While intermittent ADT is currently experimental, there is accumulating evidence demonstrating satisfactory oncologic outcomes with decreased morbidity compared to continuous treatment.     

雄激素受体在晚期前列腺癌治疗中的作用

对34例晚期前列腺癌患者在接受抗雄激素治疗前作前列腺雄激素受体（AR）定量测定，以了解AR值在抗雌激素治疗中的作用。结果发现，前列腺癌细胞浆AR（cAR）和细胞核AR（nAR）的平均值分别为71．4±65．7fmol／mg和299．4±371．8fmol／mg；nAR值在100fmol／mg以上者为58．8％，多于cAR的26．5％。随访27例患者，在激素治疗有反应的17例中，nAR＞100fmol／mg者占76.5％，与cAR的17.6％有显著性差异。而在nAR≤100fmol／mg的患者中，60％于治疗8～24个月内反应性消火。认为nAR值的变化能较准确地预测前列腺癌患者对抗雄激素治疗的反应性。     

Androgen and prostate cancer: the role of primary androgen deprivation therapy in localized prostate cancer

BackgroundThe basic mechanisms and clinical efficacy of primary androgen deprivation therapy (PADT), especially combined androgen blockade (CAB) for localized or locally advanced prostate cancer (PCa) have been outlined. An important point relates to which patients are suitable candidates for PADT.MethodsA retrospective review of the efficacy of PADT in 628 patients with localized or locally advanced PCa treated with PADT at seven institutions in Japan was carried out.ResultsIt was found that more than 30% of low- or intermediate-risk localized PCa patients could have their disease controlled over the long-term by PADT alone. Short-term or intermittent PADT could not be recommended because of the possibility of character change in the cancer cells as a result of incomplete androgen ablation.ConclusionAlgorithms are proposed for the treatment of localized PCa not only in low- and intermediate-risk groups, but also in the high-risk group. Future research directions are indicated.     

西地那非治疗勃起功能障碍的安全性和疗效的临床应用研究

目的：观察枸椽酸西地那非上市后实际临床应用中的安全性和有效性。方法：采用多中心、开放、非对照的方法，在全国36家医院对2101例因勃起功能障碍口服西地那非治疗的患者进行了观察随访。平均观察期65d(6-310d)。260例患者（12.4％）观察达6个月以上。结果；所观察到的各系统不良事件的特点和类型与说明书中所列及中国II期临床试验结果一致。未发现新的不良事件，不良事件发生率并不因服药期延长而升高。所有不良事件均为轻度至中度（以轻度为主），多数不需处理即可缓解，多于服药当天缓解。西地那非治疗勃起功能障碍的总有效率为82.3％。结论：西地那非治疗勃起功能障碍安全、有效、耐受性好。     

雄激素水平增龄变化对老年男性的影响

雄激素对机体的影响是多方面的。随着人体的衰老 ,雄激素水平会发生变化 ,这种变化对老年男性生理和心理会产生影响 ,如生殖功能、性功能、认知能力、情绪、骨骼肌肉等 ,老年男性雄激素水平的降低与临床表现之间的关系较为复杂 ,这方面的研究受很多因素的影响。对雄激素水平下降的老年男性可以给予激素替代治疗 ,但是也应对其副作用引起足够重视。     

舍曲林个体化治疗原发性早泄的疗效分析

目的 比较不同剂量舍曲林治疗原发性早泄的临床疗效.方法选择86例符合原发性早泄诊断的患者,治疗前评估国际勃起功能评分表、中国早泄患者性功能评价表.第一阶段治疗4周,每日服用盐酸舍曲林50 mg并配合行为疗法.4周后,根据疗效和不良反应将患者分为3组进入第二阶段治疗4周:有效且无或有轻微不良反应者继续原治疗;无效但无明显不良反应者,舍曲林剂量凋整为每日100 mg;有效但有明显不良反应者舍曲林剂量调整为每日25 mg;无效且有明显不良反应、不能耐受者退出观察.结果86例第一阶段4周治疗后,有效63例(73.3%),无效23例(26.7%).其中,无明显不良反应53例(61.6%),有不良反应33例(38.4%).第二阶段治疗中,有效组中35例无明显不良反应和12例有轻微不良反应者继续原治疗,16例有明显不良反应且不能耐受者舍曲林剂量调整为每日25 mg.无效组中,18例无明显不良反应者将舍曲林剂量凋整为每日100 mg,5例退出观察.8周治疗后,50 mg组47例均有效,无明显不良反应;25 mg组中有效10例,无效6例,2例有轻微不良反应且可耐受;100 mg组中有效8例(44.4%),13例(72.2%)有不良反应但可以耐受,2例因明显不良反应退出治疗,1例无效且无明显不良反应.8周总有效率80.2%(65/81),总不良反应发生率21.0%(17/81).结论舍曲林治疗原发性早泄安全有效,个体化治疗方案有效率无明显变化,不良反应发生率显著降低,患者对治疗的依从性增加.

Abstract：

Objective To compare the therapeutic effects with different dosages of sertraline on patients suffering from idiopathic premature ejaculation. Methods IIEF-5 and CIPE questionnaires were completed before the treatment, and 86 patients who met the diagnostic standard of idiopathic premature ejaculation were finally recruited. Subjects were administered sertraline 50 mg/d combined with behavior therapy at stage Ⅰ for 4 weeks. Then, according to the therapeutic effects and the adverse events, all of the patients were divided into 3 groups for stage Ⅱ (another 4 weeks) as ①subjects with good effectiveness but with no or slight adverse events,would continue the treatments ②subjects with no therapeutic effects and with no obvious adverse events were allowed to increase the dosage of sertraline to 100 mg/d;③patients with effectiveness and obvious adverse events were al follows:lowed to reduce the dosage of sertraline to 25 mg/d. Those who had obvious adverse events and no effectiveness quit the study. Results During stage Ⅰ , 63 of 86 patients were effective (73.3%), and 23 patients had no improvement (26. 7%). Thirty-three patients had adverse events (38. 4%), and the remaining 53 patients had no obvious adverse events (61.6%). During stage Ⅱ , of the patients that responded to treatment, 35 patients who had no adverse events and 12 who had slight adverse events continued the treatment. Furthermore, 16 with intolerable adverse events were allowed to reduce the dosage to 25 mg/d. Meanwhile, of those without improvement, 18 subjects without obviousadverse events were allowed to increase the dosage to 100 mg/d, and 5 patients discontinued the treatment. Eight weeks later, among the patients taking 50 mg/d, 47 subjects were effectively with no obvious adverse events. Among the patients taking 25 mg/d, 10 showed improvement, 6 showed no improvement, and 2 had tolerable slight adverse events. Among the patients taking sertraline 100 mg/d,8 witnessed effectiveness, 13 had tolerable adverse events and 2 discontinued the treatment, with 1 having neither effectiveness nor obvious adverse events. The adverse events rate was 21.0% and the total effective rate of 8 weeks of treatment was 80.2 %. Conclusions Sertraline administration is an effective and safe way to treat idiopathic premature ejaculation. Although the effectiveness of the individualized treatment had no obvious improvement comparing routine therapy, there was a notable reduction in the adverse events rate, which increased the patient compliance.     

Bone mass in androgen-insensitivity syndrome: Response to hormonal replacement therapy

The response of bone mass to long-term treatment with estrogen and progesterone in patients with complete androgen-insensitivity syndrome (AIS) is unknown. We report a 17-year-old female patient (karyotype 46 X, Y) with AIS studied during a 4-year period. Bone mineral density (BMD) measured by dual X-ray absorptiometry in lumbar spine and proximal femur was sharply reduced at the initial visit, and remained unchanged during long-term follow-up on hormone replacement therapy with estrogens and progestin. Bone metabolism markers were all in the normal range. The lack of significant increase in BMD highlights the importance of androgens on bone physiology that cannot be balanced in spite of an appropriate estrogenic milieu.     

Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy

Background

With salvage radiation therapy (SRT) in the postprostatectomy setting, the need to deliver sufficient radiation doses to achieve a high probability of tumor control is balanced with the risk of increased toxicity. Intensity-modulated radiation therapy (IMRT) in the postprostatectomy salvage setting is gaining interest as a treatment strategy.

Objective

Compare acute and late toxicities in patients treated with IMRT and three-dimensional conformal radiation therapy (3D-CRT) in the postprostatectomy salvage setting.

Design, setting, and participants

A total of 285 patients who were treated at our institution between 1988 and 2007 with SRT after radical prostatectomy for biochemical recurrence were identified. All medical records were reviewed and toxicity recorded. Median follow-up was 60 mo.

Intervention

All patients were treated with SRT with either 3D-CRT (n = 109) or IMRT (n = 176). A total of 205 patients (72%) were treated with doses ≥70 Gy.

Measurements

Late gastrointestinal (GI) and genitourinary (GU) toxicities were recorded using the Common Terminology Criteria for Adverse Events v. 3.0 definition.

Results and limitations

The 5-yr actuarial rates of late grade ≥2 GI and GU toxicity were 5.2% and 17.0%, respectively. IMRT was independently associated with a reduction in grade ≥2 GI toxicity compared with 3D-CRT (5-yr IMRT, 1.9%; 5-yr 3D-CRT, 10.2%; p = 0.02). IMRT was not associated with a reduction in risk of grade ≥2 GU toxicity (5-yr IMRT, 16.8%; 5-yr 3D-CRT, 15.8%; p = 0.86), urinary incontinence (5-yr IMRT, 13.6%; 5-yr 3D-CRT, 7.9%; p = 0.25), or grade 3 erectile dysfunction (5-yr IMRT, 26%; 5-yr 3D-CRT, 30%; p = 0.82). Of patients who developed late grade ≥2 GI or GU toxicity, 38% and 44%, respectively, experienced resolution of their symptoms prior to the last follow-up.

Conclusions

Our experience with high-dose IMRT in the postprostatectomy salvage setting demonstrates that the treatment can be delivered safely with an associated reduction in late GI toxicity.     

衰老对大鼠阴茎海绵体NOS I的表达和NOS活性的影响

目的 :探讨衰老对大鼠阴茎海绵体一氧化氮合酶Ⅰ (NOSⅠ)mRNA、蛋白的表达和NOS活性的影响。　方法 :30只雄性SD大鼠按不同月龄分为成年组、老年组和衰老组 ,应用Western印迹、RT PCR方法分别检测不同年龄组阴茎海绵体NOSⅠ蛋白及mRNA的表达 ;用紫外分光光度计测定不同年龄组阴茎海绵体NOS的活性。　结果 :成年组NOSⅠ 蛋白的表达量最高 ,老年组和衰老组显著降低 ,分别为成年组的 75 .6 %和 6 1.2 % ;NOSⅠmRNA的表达与蛋白表达的变化一致 ;老年组NOS活性与成年组差异无显著性 (P >0 .0 5 ) ,衰老组NOS活性明显降低 ,是成年组的70 .4 % ,并且差异非常显著 (P <0 .0 1)。　结论 :衰老引起NOSⅠ 蛋白及mRNA的表达降低和NOS活性的显著降低 ,可能是老年性阴茎勃起功能障碍的主要机制之一。     

衰老对大鼠阴茎海绵体NOSⅠ的表达和NOS活性的影响

目的 :探讨衰老对大鼠阴茎海绵体一氧化氮合酶Ⅰ (NOSⅠ)mRNA、蛋白的表达和NOS活性的影响。　方法 :30只雄性SD大鼠按不同月龄分为成年组、老年组和衰老组 ,应用Western印迹、RT PCR方法分别检测不同年龄组阴茎海绵体NOSⅠ蛋白及mRNA的表达 ;用紫外分光光度计测定不同年龄组阴茎海绵体NOS的活性。　结果 :成年组NOSⅠ 蛋白的表达量最高 ,老年组和衰老组显著降低 ,分别为成年组的 75 .6 %和 6 1.2 % ;NOSⅠmRNA的表达与蛋白表达的变化一致 ;老年组NOS活性与成年组差异无显著性 (P >0 .0 5 ) ,衰老组NOS活性明显降低 ,是成年组的70 .4 % ,并且差异非常显著 (P <0 .0 1)。　结论 :衰老引起NOSⅠ 蛋白及mRNA的表达降低和NOS活性的显著降低 ,可能是老年性阴茎勃起功能障碍的主要机制之一。     

Testosterone and Erection: Practical Management for the Patient with Erectile Dysfunction

Although erectile dysfunction (ED) and testosterone deficiency syndrome are two independently distributed disorders, there is a degree of overlap between them. Testosterone replacement therapy, either alone or combined with other treatments such as a phosphodiesterase type 5 (PDE5) inhibitor, may therefore be useful in some men with ED. Corrective treatment of ED includes sex therapy, risk factor modification, chronic usage of PDE5 inhibitors, and testosterone replacement. Studies have shown that testosterone replacement in men with hypogonadism improves libido and erectile function in a significant proportion of cases. If corrective treatment fails or is not indicated, symptomatic treatments such as oral PDE5 inhibitors or intraurethral/intracavernous therapy are available. PDE5 inhibitors are an excellent first-line choice, although a significant proportion of men still fail to respond to monotherapy. Testosterone deficiency may be overlooked in some men with ED and, because this may be associated with lower expression of PDE5 in the penis, it could result in failure of PDE5 inhibitor therapy. Recent recommendations, therefore, suggest the need for combination therapy in some patients. In conclusion, all men presenting with ED should have their testosterone levels checked, and testosterone replacement should be considered in those with low levels. Testosterone replacement should also be considered in hypogonadal men with ED not responding to PDE5 inhibitors. If erections remain insufficient after 3 mo, a combination of testosterone and a PDE5 inhibitor may be beneficial.     

Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial

Background

The cornerstone of standard treatment for patients with primary bone metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT). Retrospective studies suggest a survival benefit for treatment of the primary prostatic tumour in mPCa, but to date, no randomised-controlled-trials (RCTs) have been published addressing this issue.

连续性肾脏替代治疗多脏器功能衰竭的疗效

目的 分析连续性肾脏替代治疗(continuous renal replacement therapy,CRRT)对多脏器功能衰竭患者的疗效.方法 回顾性分析30例多脏器功能衰竭患者的临床资料,探讨CRRT治疗多脏器功能衰竭的疗效.结果 30例多脏器功能衰竭患者中15例痊愈,5例存活,10例死亡.结论 多脏器功能衰竭是临床上的急危重症,发病凶险,死亡率高,CRRT对多脏器功能衰竭患者有很好的疗效.     

西地那非治疗勃起功能障碍的现状

简要介绍了西地那非的药理作用机制 ,着重阐述了该药对勃起功能障碍 (ED)的治疗效果及安全性 ,特别对高血压及服用抗高血压药物病人、心脏病病人、糖尿病病人、脊髓损伤病人、前列腺根治性手术后病人、长期透析病人等特殊人群的应用情况进行总结。西地那非对ED的治疗总体上有效、安全。     

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。