成年男性IHH的遗传筛查和GnRH脉冲泵治疗研究

发布时间：2018-05-15 03:33

本文选题：特发性低促性腺激素性性腺功能减退症 + 致病基因　；参考：《第三军医大学》2017年硕士论文

【摘要】：研究背景:特发性低促性腺激素性性腺功能减退症(idiopathic hypogonadotrpic hypogonadism,IHH)是指因先天性下丘脑促性腺激素释放激素(Gn RH)神经元功能受损,GnRH合成、分泌或作用障碍,导致垂体分泌促性腺激素减少,进而引起性腺功能不足的一类疾病。IHH发病率男性为1/1万,女性为1/5万。随着人们对于其病因学认识的不断发展和进步,目前IHH已被证实是一类基因遗传性疾病,同时越来越多的IHH相关性基因被发现。男性IHH患者常因生理上缺陷而心理自卑,严重影响正常社交与正常婚恋,造成家庭、社会负担。针对男性IHH患者存在第二性征发育异常,青春期性成熟推迟/终止,生精功能障碍等问题,传统的促性腺激素治疗方法,需要长期规律性进行肌肉注射治疗,存在治疗繁琐,疗程长,患者难以坚持等缺点。近年来新出现的Gn RH微量泵自动脉冲式输注治疗的方法,为IHH患者提供了更加理想的治疗措施。Gn RH脉冲泵模拟人体Gn RH生理脉冲,更加符合机体自身下丘脑-垂体-性腺调节轴的生理性调节机制,但其临床应用经验尚少,长期治疗对男性外生殖器发育的改善,对男性生殖能力和性功能恢复的影响等尚缺乏系统深入研究。研究目的:评价Gn RH微量泵脉冲治疗成年男性IHH患者的中远期疗效与安全性;通过对IHH患者遗传因素的筛查,探讨患者遗传因素与Gn RH脉冲泵治疗有效性之间的相关性,从而寻求成年男性IHH的最佳治疗策略。研究方法:选择从2013年8月至2016年12月就诊于我院,符合IHH诊断标准,GnRH兴奋试验确定垂体,性腺反应性良好的成年男性患者共30例,采用前瞻性自身对照研究方法,首先记录患者治疗前临床特征、性激素检查结果,然后采用GnRH微量泵进行治疗,于治疗期间不同时间段,如3,6,12个月分别对患者进行严格随访观察并详细记录患者治疗期间的一般性特征变化、性激素及促性腺激素变化、外生殖器形态大小变化、精液数质量变化,统计分析IHH患者采用GnRH泵治疗的中远期疗效,同时了解患者在GnRH泵治疗期间所出现的不良事件。对IHH患者进行相关致病基因筛查,并结合临床,分析致病基因与临床疗效的相关性。研究结果:本研究纳入30位患者,平均随访时间15.9(2-40)个月,治疗1年以上20例,半年~1年3例,3月~半年4例,3月以下3例。患者治疗前睾丸体积(3.43±1.94)ml,黄体生成素(LH)(0.66±0.60)IU/L,卵泡刺激素(FSH)(1.25±0.85)IU/L,睾酮(T)(0.50±0.51)ng/ml,阴茎牵长(5.77±1.47)cm,阴茎静息长度(3.68±1.06)cm,阴茎周径(5.16±1.31)cm;带泵治疗半年患者睾丸体积(6.55±2.13)ml,LH(6.60±5.10)IU/L,FSH(5.36±3.10)IU/L,T(2.32±1.31)ng/ml,阴茎牵长(7.93±1.22)cm,阴茎静息长度(4.91±0.81)cm,阴茎周径(7.21±1.29)cm,均较治疗前有显著提高(p0.01)。带泵治疗1年以上患者睾丸体积(8.93±2.40)ml,LH(6.20±3.86)IU/L,FSH(4.93±2.38)IU/L,T(3.59±1.03)ng/ml,阴茎牵长(9.29±1.45)cm,阴茎静息长度(5.82±0.77)cm,阴茎周径(8.13±0.97)cm,均较治疗前有显著提高(p0.01),外生殖器大小、T水平较半年前有进一步显著改善提高(p0.05)。治疗前30例患者无手淫,无遗精,仅有2例患者有遗精(精液中无精子),治疗半年以上23例患者均相继出现遗精并伴经常性勃起,其中20例患者取得精液,16例出现精子,2例已婚患者配偶自然妊娠。所有患者治疗期间未见明显不良反应,患者依从性良好。14例患者自愿行基因检测,2例患者发现明确致病基因,2例发现错义突变和1例发现同义突变(临床意义不明)。由于本研究所发现存在致病基因例数较少,暂无法得出存在致病基因与否和临床疗效好坏之间的明确相关性。研究结论:GnRH脉冲泵治疗成年男性IHH,中远期疗效理想,安全性良好,是IHH患者的首选治疗方案。
[Abstract]:Background: idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotrpic hypogonadism, IHH) refers to the impairment of the function of Gn RH neurons in the congenital hypothalamus (Gn RH), the synthesis, secretion, or dysfunction of GnRH, which leads to the secretion of gonadotropin in the pituitary and then the insufficiency of the gonadotropin. The incidence of.IHH in a class of diseases is 1/1 million and 1/5 million for women. With the continuous development and progress of people's knowledge of etiology, IHH has been proved to be a genetic hereditary disease, and more and more IHH related genes are found. Male IHH patients often suffer from psychological inferiority because of physiological defects, which seriously affect normal social and social conditions. Normal marriage and love cause family and social burden. For male IHH patients, there are problems of abnormal development of secondary sex syndrome, delayed sexual maturity, termination of puberty, and spermatogenic dysfunction. The traditional method of gonadotropin therapy requires long-term regularity of intramuscular injection therapy, which has some shortcomings in recent years, such as tedious treatment, long treatment process, and hard to insist on patients. The new method of Gn RH micro pump automatic pulse infusion therapy provides a more ideal treatment for IHH patients with.Gn RH pulse pump to simulate human Gn RH physiological pulse, which is more in line with the physiological regulation mechanism of the hypothalamus pituitary gonad axis adjustment axis of the body itself, but the experience of its application to the bed is few, and the long-term treatment for male exogeny Lack of systematic and in-depth study on the effects of colonization development on male reproductive capacity and sexual function recovery. Objective: To evaluate the long-term efficacy and safety of Gn RH micropump pulse therapy in the treatment of adult male IHH patients; to explore the genetic factors of patients with IHH and the efficacy of Gn RH pulse pump in the treatment of patients. To seek the best treatment strategy of adult male IHH. Study methods: select from August 2013 to December 2016 in our hospital, conform to the IHH diagnostic criteria, GnRH excitation test to determine the pituitary, 30 adult male patients with good gonadal reactivity, using a prospective self-control study, first record the patients before treatment. The clinical features, the results of the sex hormone examination, and then the GnRH micropump. During the treatment, the patients were followed up and observed at different time periods, such as 3,6,12 months, and recorded the general characteristics of the patients during the treatment, the changes of sex hormone and gonadotropin, the change of the shape and size of the genitals, the quality of the semen. The IHH patients were treated with the GnRH pump for the middle and remote effect, and the adverse events occurred during the GnRH pump treatment. The related genes were screened for the IHH patients and the correlation between the pathogenetic genes and the clinical efficacy was analyzed. The results were included in the study. The study included 30 patients with an average follow-up time of 15.9 (2-4 0 months, 20 cases for more than 1 years, 3 six months ~1 year, 4 cases in March to six months and 3 cases below March. The volume of testis before treatment (3.43 +. 1.94), LH (0.66 + 0.60) IU/L, follicle stimulating hormone (1.25 + 0.85), T (0.50 +) ng/ml, penile stretch (3) cm, penile resting length (3) cm, penis circumference diameter 1.31) cm (6.55 + 2.13), LH (6.60 + 5.10) IU/L, FSH (5.36 + 3.10) IU/L, T (2.32 + 1.31) ng/ml, penile stretch (7.93 + 1.22) cm, penis resting length (4.91 + 0.81) cm and penile circumference cm, both were significantly higher than before treatment (P0.01). (6.20 + 3.86) IU/L, FSH (4.93 + 2.38) IU/L, T (3.59 + 1.03) ng/ml, penile stretch (9.29 + 1.45) cm, penis resting length (5.82 + 0.77) cm, and penis circumference (8.13 + 0.97) cm, which were significantly higher than before treatment (P0.01), the size of the external genitals, T levels were further improved (P0.05) than before half a year. No masturbation, no remains before treatment before treatment. Only 2 patients had spermatospermia (spermatospermia in semen), 23 of them had spermatozoa and frequent erectile, of which 20 had semen, 16 had spermatozoa and 2 married couples had natural pregnancies. All patients had no obvious adverse reactions during the treatment. Patients with good compliance,.14 patients voluntarily performed genes. 2 patients found clear pathogenic genes, 2 cases found missense mutation and 1 cases of synonymous mutation (clinical significance). Because the number of pathogenic genes found in this study was less, there was no clear correlation between the existence of pathogenic genes and the clinical efficacy. Conclusion: GnRH pulse pump was used to treat adult male IHH, Medium and long term curative effect is ideal and safe. It is the first choice for IHH patients.

【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R588

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