重组人生长激素治疗男性更年期及性功能减退疗效的临床研究
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摘要
前言
随着年龄的增大，男性的内分泌轴也随之发生变化。1)下丘脑—垂体—睾酮轴，变化在于睾酮水平下降，LH和FSH升高。2)下丘脑—垂体—肾上腺轴：脱羟表雄酮(DHEA)和其硫酸盐(DHEA-S)逐步减少。3)GH—IGF轴：生长激素GH合成减少，出现类似成人GH缺乏症状。但是，上述变化缺乏可靠临床指标来诊断和指导治疗。相比较于女性绝经期有着明确的定义，男性内分泌系统的衰老是逐步的、个体差异较大的过程。与上述内分泌轴想对应的部分内分泌激素包括外周睾酮水平、脱羟表雄酮(DHEA)及其硫酸盐(DHEA-S)、生长激素(GH)、胰岛素样生长因子(IGF)及褪黑素都趋于减少。
中老年男子部分性雄激素缺乏综合症(Partial Androgen Deficiency in the Aging Male，PADAM)指男子生物雄激素分泌在青年期达到高峰后逐渐下降这一事实，一部分男子在50岁前后出现雄激素缺乏的临床症状。其发病率伴随着年龄的增长
浙江大学硕士学位论文
而增高。勃起功能障碍(Ereetile Dysfunction，简称ED)，通常表现为勃起功能不
同程度的减退。调查发现40~70岁的男性ED发病率是52%，这一结果提示勃起
功能障碍是老年男性的常见病。
生长激素GH是由腺垂体内的生长素细胞分泌，由191个氨基酸残基组成，
GH促进物质代谢与生长发育，对机体各个器官与多种组织均有影响，尤其是对骨
骼、肌肉和内脏器官。近来的研究表明GH对性功能的影响由IGF一1介导刺激内
皮来源形成NO。在阴茎充血的状态下，测得体循环和海绵体中的GH浓度均显著
升高。另有实验提示GH能明显促进盆神经结内含NOS神经元的数量，并且刺激
从神经元再生出含NOS的神经纤维。重组人生长激素(thGH)，是通过重组DNA
技术将编码人GH的基因导入大肠杆菌而取得的基因工程产品。较之以往的GH
制剂的优点在于纯度更高、特异活性更强、成分均质性更高以及理论上可无限量
供应。，
本实验主要通过酶联免疫吸附法检测胰岛素样生长因子(IGF一1)，选用国际
勃起功能指数问卷(nEF)和伊斯坦布尔BosPhorus男性更年期自我评定表来研究
重组人生长激素针剂(thGH)改善中老年男性更年期症状及性功能减退症状的有
效性和安全性，并探讨IGF一1作为诊断男性更年期症状和判断GH补充治疗疗效
指标的特异性和敏感性。
材料和方法
1、病例来源:于浙江大学附属第一医院泌尿外科门诊收集以性功能减退或(和)
男性衰老症状就诊的患者，要求40一75岁，共20例。另收集20例40岁以下的
浙江大学硕士学位论文
正常男性，采集血清标本测定IGF一1值。
2、实验步骤:首先经过4周的准备期，收集患者基线时的性功能等数据，符合入
选标准者被随机地分配到A组或B组，进入为期12周的治疗。A组患者每周肌
肉注射rhGH4IU(rhGH4川一次，同等剂量生理盐水一次，每周各一次，时间相
隔3一4天);B组患者每周注射重组人生长激素SIU(每次4川，每周2次，相隔
3一4天);均持续12周。治疗期间，每4周进行I正F、男性更年期自我评定表问
询;对患者实验前后各项实验室检查指标(包括IGF一l)进行采集。对患者试验
不同访视阶段的IIEF评分、nEF一5评分、男性更年期自我评定表评分进行采集。
对患者诉说的其他疗效和副作用加以归纳。
3、统计学分析:所有资料用统计软件SPSSll.O处理。对各阶段的nEF总分及分
项评分、男性更年期评表总分及分项评分、研究前后患者实验室指标进行配对T
检验;对正常人群、患者研究前后的IGF一1水平进行
检验;对研究前后
的nEF总分差值、男性更年期总分差值、IGF一1差值作关于年龄、剂量的析因分
结果
经研究前后项比较，A组更年期症状临床总有效率(轻度改善+明显改善)
为80%;性功能减退改善总有效率为55.6%(轻度改善+明显改善)。B组更年期
症状临床总有效率为100%;性功能减退症状改善临床总有效率为70%。rhGH改
善中老年更年期症状主要体现在对血管舒缩症状、体能状况、性功能症状方面，
在用药1月起效，用药3月效果最佳。疗效与用药剂量、患者年龄分段无明显相
浙江大学硕士学位论文
关。rhGH改善中老年性功能减退症状体现在增强勃起硬度和延长持续勃起时间，
在用药l月起效，用药2月达到最大疗效，与剂量呈正相关，与年龄呈负相关。
患者研究前IGF一1水平与正常人群无显著差异，用药后IGF一1水平高于研
究前水平，也高于正常人群水平;增高的IGF一1水平与疗效平行。
thGH治疗期间未发现严重副作用，安全性较好。
结论
1、小剂量重组人生长激素能显著改善中老年男性更年期症状，并且与剂量、患者
年龄无相关关系。
2、小剂量重组人生长激素能显著改善中老年男性性功能，并且与剂量呈正相关，
与患者年龄呈负相关。
3、小剂量重组人生长激素能显著提高中老年男性IGF一1水平，并且与年龄呈负
相关，与GH用药剂量无关。
4、IGF一1测量值可以作为应用重组人生长激素疗效判断的指标之一。
5、成人短期应用重组人生长激素安全性好，副作用小。
6、成人短期应用重组人生长激素不会增加前列腺增生及前列腺癌的风险。
The three endocrine axes change as male grow aged. (1) Hypothalamus-Hypophysis- Testosterone axis, the level of testosteone drops as well as the LH and FSH elevate. (2) Hypothalamus- Hypophysis-Adrenal axis, the DHEA and DHEA-Sulfate secrete less. (3)CH-IGF-1 axis, the GH's level decrease and synptomes appear as the Adult GH deficiency Syndrome. However, the clinic nowdays do not find out the methods to detect the endocrine axes changes, therefore, it is difficult to diagnosis and treat the symptoms followed by the endocrine changes. Compairing the female menopause has the exact definitions, the male endocrine changes gradually and variably. And parts of hormone, such as the testosterone, DHEA, DHEA-S, GH, IGF-1 and melatonin become less.
The PADAM, Partial Androgen Deficiency in the Aging Male, is referred as the symptoms followed the decreased level of testostrone, mostly after 50 years old. The incidence rate becomes more as the male growes older. The Erectile Dysfunction is defined as the varied decline of erectile function. One survey demonstrated that the incidence rate of ED in male from 40 years to 70 is about 52%, and so ED is commom to the aged male.
The growth hormone (GH) is secreted by the somatin cell in the glandular pituitary and composed by 191 amino acid residues. The GH can accelerate the metabolism and promote growth by affect many organs and tissue, especially to the bone, muscle and viscera organs. In details, GH promote the osteoblast, accelerate the synthesis of protein and oxidation of lipid, as well as result in a comparative high level of blood glucose. Recent studies showed that GH could develop erectile function by stimulation the synthesis of endothelial derived NO. In the erectile state, the concentration of GH both in the circulation and the cavernosum becomes obviously high. Another study indicted that the GH could promote the quantity of NO-containing neuron in the pelvic ganglia, and moreover, GH promote the regeneration of nerve fiber derived from neuron. The recombinant human growth hormone (rhGH) is the product of gene engineering project, transferred the GH gene into animal cell by the recombinant DNA technique. It is of high purity and activity, and can be provided endless, at least in theory.
This study aims in the efficacy and safety of recombinant human growth hormone (rhGH) for improvements at symptoms in male menopause and impaired sexual dysfunction, by testing the IGF-1 using the ELISA method, and chosing the HEF and Istanbul Bosphorus's Instrument for estimate the male andropause and aging. Moreover, we try to evaluate the specifity and sensitivity of IGF-1 as a marker to detect the male age and direct the GH supply treatment
MATERIALS AND METHODS
We collect 20 patients in the Urological and Andrological clinic of the first affiliated hospital of Zhejiang University, medical college with the chief complaints of suffering from ED or (and) male andropause symptoms as well as 20 normal males younger than 40 years old.
The patients would be prepared for 4 weeks to collecting the datas about the Adropause and sexual disfunction as the baseline levels. After the labotory examinations, we choose the prompt volunteers as the cases, and devide them into group A and B by random. In group A, the patients would accept the rhGH injectiuon once a week as well as sodium solution once. In group B, they would receive two times injection of rhGH a week. Every four weeks since the study, we would ask the cases about the improvements in andropause and sexual function with the the IIEF and Male Andropause Self-estimate Tablet. The injection would last for 12 weeks till the repeated examinations, including the IGF-1 of the normal
cases and the patients.
All the datas will be treated by the statistic SPSS 11.0. The Paired T test will be applied in the IIEF total points and partial points as well as the Male Andropause Self-estimate Tablet. The labotary examinations before and after the study will be processed as the IIEF points. The IGF-1 levels will be analyzed by
随着年龄的增大，男性的内分泌轴也随之发生变化。1)下丘脑—垂体—睾酮轴，变化在于睾酮水平下降，LH和FSH升高。2)下丘脑—垂体—肾上腺轴：脱羟表雄酮(DHEA)和其硫酸盐(DHEA-S)逐步减少。3)GH—IGF轴：生长激素GH合成减少，出现类似成人GH缺乏症状。但是，上述变化缺乏可靠临床指标来诊断和指导治疗。相比较于女性绝经期有着明确的定义，男性内分泌系统的衰老是逐步的、个体差异较大的过程。与上述内分泌轴想对应的部分内分泌激素包括外周睾酮水平、脱羟表雄酮(DHEA)及其硫酸盐(DHEA-S)、生长激素(GH)、胰岛素样生长因子(IGF)及褪黑素都趋于减少。
中老年男子部分性雄激素缺乏综合症(Partial Androgen Deficiency in the Aging Male，PADAM)指男子生物雄激素分泌在青年期达到高峰后逐渐下降这一事实，一部分男子在50岁前后出现雄激素缺乏的临床症状。其发病率伴随着年龄的增长
浙江大学硕士学位论文
而增高。勃起功能障碍(Ereetile Dysfunction，简称ED)，通常表现为勃起功能不
同程度的减退。调查发现40~70岁的男性ED发病率是52%，这一结果提示勃起
功能障碍是老年男性的常见病。
生长激素GH是由腺垂体内的生长素细胞分泌，由191个氨基酸残基组成，
GH促进物质代谢与生长发育，对机体各个器官与多种组织均有影响，尤其是对骨
骼、肌肉和内脏器官。近来的研究表明GH对性功能的影响由IGF一1介导刺激内
皮来源形成NO。在阴茎充血的状态下，测得体循环和海绵体中的GH浓度均显著
升高。另有实验提示GH能明显促进盆神经结内含NOS神经元的数量，并且刺激
从神经元再生出含NOS的神经纤维。重组人生长激素(thGH)，是通过重组DNA
技术将编码人GH的基因导入大肠杆菌而取得的基因工程产品。较之以往的GH
制剂的优点在于纯度更高、特异活性更强、成分均质性更高以及理论上可无限量
供应。，
本实验主要通过酶联免疫吸附法检测胰岛素样生长因子(IGF一1)，选用国际
勃起功能指数问卷(nEF)和伊斯坦布尔BosPhorus男性更年期自我评定表来研究
重组人生长激素针剂(thGH)改善中老年男性更年期症状及性功能减退症状的有
效性和安全性，并探讨IGF一1作为诊断男性更年期症状和判断GH补充治疗疗效
指标的特异性和敏感性。
材料和方法
1、病例来源:于浙江大学附属第一医院泌尿外科门诊收集以性功能减退或(和)
男性衰老症状就诊的患者，要求40一75岁，共20例。另收集20例40岁以下的
浙江大学硕士学位论文
正常男性，采集血清标本测定IGF一1值。
2、实验步骤:首先经过4周的准备期，收集患者基线时的性功能等数据，符合入
选标准者被随机地分配到A组或B组，进入为期12周的治疗。A组患者每周肌
肉注射rhGH4IU(rhGH4川一次，同等剂量生理盐水一次，每周各一次，时间相
隔3一4天);B组患者每周注射重组人生长激素SIU(每次4川，每周2次，相隔
3一4天);均持续12周。治疗期间，每4周进行I正F、男性更年期自我评定表问
询;对患者实验前后各项实验室检查指标(包括IGF一l)进行采集。对患者试验
不同访视阶段的IIEF评分、nEF一5评分、男性更年期自我评定表评分进行采集。
对患者诉说的其他疗效和副作用加以归纳。
3、统计学分析:所有资料用统计软件SPSSll.O处理。对各阶段的nEF总分及分
项评分、男性更年期评表总分及分项评分、研究前后患者实验室指标进行配对T
检验;对正常人群、患者研究前后的IGF一1水平进行
检验;对研究前后
的nEF总分差值、男性更年期总分差值、IGF一1差值作关于年龄、剂量的析因分
结果
经研究前后项比较，A组更年期症状临床总有效率(轻度改善+明显改善)
为80%;性功能减退改善总有效率为55.6%(轻度改善+明显改善)。B组更年期
症状临床总有效率为100%;性功能减退症状改善临床总有效率为70%。rhGH改
善中老年更年期症状主要体现在对血管舒缩症状、体能状况、性功能症状方面，
在用药1月起效，用药3月效果最佳。疗效与用药剂量、患者年龄分段无明显相
浙江大学硕士学位论文
关。rhGH改善中老年性功能减退症状体现在增强勃起硬度和延长持续勃起时间，
在用药l月起效，用药2月达到最大疗效，与剂量呈正相关，与年龄呈负相关。
患者研究前IGF一1水平与正常人群无显著差异，用药后IGF一1水平高于研
究前水平，也高于正常人群水平;增高的IGF一1水平与疗效平行。
thGH治疗期间未发现严重副作用，安全性较好。
结论
1、小剂量重组人生长激素能显著改善中老年男性更年期症状，并且与剂量、患者
年龄无相关关系。
2、小剂量重组人生长激素能显著改善中老年男性性功能，并且与剂量呈正相关，
与患者年龄呈负相关。
3、小剂量重组人生长激素能显著提高中老年男性IGF一1水平，并且与年龄呈负
相关，与GH用药剂量无关。
4、IGF一1测量值可以作为应用重组人生长激素疗效判断的指标之一。
5、成人短期应用重组人生长激素安全性好，副作用小。
6、成人短期应用重组人生长激素不会增加前列腺增生及前列腺癌的风险。
The three endocrine axes change as male grow aged. (1) Hypothalamus-Hypophysis- Testosterone axis, the level of testosteone drops as well as the LH and FSH elevate. (2) Hypothalamus- Hypophysis-Adrenal axis, the DHEA and DHEA-Sulfate secrete less. (3)CH-IGF-1 axis, the GH's level decrease and synptomes appear as the Adult GH deficiency Syndrome. However, the clinic nowdays do not find out the methods to detect the endocrine axes changes, therefore, it is difficult to diagnosis and treat the symptoms followed by the endocrine changes. Compairing the female menopause has the exact definitions, the male endocrine changes gradually and variably. And parts of hormone, such as the testosterone, DHEA, DHEA-S, GH, IGF-1 and melatonin become less.
The PADAM, Partial Androgen Deficiency in the Aging Male, is referred as the symptoms followed the decreased level of testostrone, mostly after 50 years old. The incidence rate becomes more as the male growes older. The Erectile Dysfunction is defined as the varied decline of erectile function. One survey demonstrated that the incidence rate of ED in male from 40 years to 70 is about 52%, and so ED is commom to the aged male.
The growth hormone (GH) is secreted by the somatin cell in the glandular pituitary and composed by 191 amino acid residues. The GH can accelerate the metabolism and promote growth by affect many organs and tissue, especially to the bone, muscle and viscera organs. In details, GH promote the osteoblast, accelerate the synthesis of protein and oxidation of lipid, as well as result in a comparative high level of blood glucose. Recent studies showed that GH could develop erectile function by stimulation the synthesis of endothelial derived NO. In the erectile state, the concentration of GH both in the circulation and the cavernosum becomes obviously high. Another study indicted that the GH could promote the quantity of NO-containing neuron in the pelvic ganglia, and moreover, GH promote the regeneration of nerve fiber derived from neuron. The recombinant human growth hormone (rhGH) is the product of gene engineering project, transferred the GH gene into animal cell by the recombinant DNA technique. It is of high purity and activity, and can be provided endless, at least in theory.
This study aims in the efficacy and safety of recombinant human growth hormone (rhGH) for improvements at symptoms in male menopause and impaired sexual dysfunction, by testing the IGF-1 using the ELISA method, and chosing the HEF and Istanbul Bosphorus's Instrument for estimate the male andropause and aging. Moreover, we try to evaluate the specifity and sensitivity of IGF-1 as a marker to detect the male age and direct the GH supply treatment
MATERIALS AND METHODS
We collect 20 patients in the Urological and Andrological clinic of the first affiliated hospital of Zhejiang University, medical college with the chief complaints of suffering from ED or (and) male andropause symptoms as well as 20 normal males younger than 40 years old.
The patients would be prepared for 4 weeks to collecting the datas about the Adropause and sexual disfunction as the baseline levels. After the labotory examinations, we choose the prompt volunteers as the cases, and devide them into group A and B by random. In group A, the patients would accept the rhGH injectiuon once a week as well as sodium solution once. In group B, they would receive two times injection of rhGH a week. Every four weeks since the study, we would ask the cases about the improvements in andropause and sexual function with the the IIEF and Male Andropause Self-estimate Tablet. The injection would last for 12 weeks till the repeated examinations, including the IGF-1 of the normal
cases and the patients.
All the datas will be treated by the statistic SPSS 11.0. The Paired T test will be applied in the IIEF total points and partial points as well as the Male Andropause Self-estimate Tablet. The labotary examinations before and after the study will be processed as the IIEF points. The IGF-1 levels will be analyzed by
引文
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2. Schulman C, Lunenfeld B. The ageing male. World-J-Urol. 2002, 20(1): 4-10
3．李江源，中国中老年男子部分性雄激素缺乏综合症诊断、治疗和监测的基本原则。中国男科学杂志，2002，17：66-68
4. Feldman HA, Goldstein I, Mckinlay JB. Impotence and its medical and psychosocial results correlate: results of the Massachusetts Male Aging Study. Jurol, 1994, 151(1): 54-61
5. Becker, Armin J, ückert, et al. Serum levels of human growth hormone during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction. Urology, 2002, 59(4): 609-614
6. Yung GW, Spencer EM, Lue TF. Growth hormone enhances regeneration of nitric oxide synthase-containing penile nerves after cavernous nerve neurotomy in rats. J-Urol. 1998, 160(5): 1899-1904
7．郭应禄，朱积川，潘天明等，口服西地那非治疗勃起功能障碍疗效和安全性的
临床研究。中华泌尿外科杂志，2001，22(7)：389-395
8. Riley AJ, Peer M, Willson C. NIH consensus development panel on impotence, JAMA, 1993, 270: 83-90
9. Muniyappa R., Walsh MF, Rangi JS, et al. Insulin like growth factor 1 increases vascular smooth muscle nitric oxide production. Life Sciences Including Pharmacology Letters. 1997, 61(9): 925-931
10. Reppert SM. & Weaver DR. Melatonin madness. Cell, 1995, 83:1059-1062
11. Xiaowei Xu, Sonntag, William E. Growth Hormone and Aging: Regulation, Signal Transduction and Replacement Therapy. Trends in Endocrinology and Metabolism. 1996, 7(4): 145-150
12. Martin H, Peter B. Hormone replacement in the aging male? Experimental Gerontology. 1999, 34: 923-933.
13. Pagel I, Langeniekel T; Hohnel K, et al. Cardiac and renal effects of growth hormone in volume overload-induced heart failure: role of NO. Hypertension. 2002, 39(1): 57-62
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