Treatment of central precocious puberty by GnRH analogs： long-term outcome in men

In boys, central precocious puberty （CPP） is the appearance of secondary sex characteristics driven by pituitary gonadotropin secretion before the age of 9 years. In the last years, relevant improvements in the treatment of CPP have been achieved. Because CPP is rare in boys, the majority of papers on this issue focus on girls and do not address specific features of male patients regarding end results and safety. In the present paper, recent advances of CPP management with GnRH analogs in men are summarized. End results in untreated and treated patients are also reviewed by an analysis of the recently published literature on treatment of CPP in men. The available data indicate that therapy with GnRH analogs can improve final height into the range of target height without significant adverse short-term and long-term effects, but longer follow-up of larger series of patients is still required to draw definitive conclusions.

Efficacy and safety of human chorionic gonadotropin combined with human menopausal gonadotropin and a gonadotropin-releasing hormone pump for male adolescents with congenital hypogonadotropic hypogonadism

Background:Compared to adult studies,studies which involve the treatment of pediatric congenital hypogonadotropic hypogonadism(CHH)are limited and no universal treatment regimen is available.The aim of this study was to evaluate the feasibility of human chorionic gonadotropin(hCG)/human menopausal gonadotropin(hMG)therapy for treating male adolescents with CHH.Methods:Male adolescent CHH patients were treated with hCG/hMG(n=20)or a gonadotropin-releasing hormone(GnRH)pump(n=21).The treatment was divided into a study phase(0-3 months)and a follow-up phase(3-12 months).The testicular volume(TV),penile length(PL),penis diameter(PD),and sex hormone levels were compared between the two groups.The TV and other indicators between the groups were analyzed using a t-test(equal variance)or a rank sum test(unequal variance).Results:Before treatment,there was no statistical difference between the two groups in terms of the biochemistry,hormones,and other demographic indicators.After 3 months of treatment,the TV of the hCG/hMG and GnRH groups increased to 5.1±2.3 mL and 4.1±1.8 mL,respectively;however,the difference was not statistically significant(P>0.05,t=1.394).The PL reached 6.9±1.8 cm and 5.1±1.6 cm(P<0.05,t=3.083),the PD reached 2.4±0.5 cm and 2.0±0.6 cm(P<0.05,t=2.224),respectively,in the two groups.At the end of 6 months of treatment,biomarkers were in normal range in the two groups.Compared with the GnRH group,the testosterone(T)level and growth of PL and PD were significantly greater in the hCG/hMG group(all P<0.05).While the TV of both groups increased,the difference was not statistically significant(P>0.05,t=0.314).After 9 to 12 months of treatment,the T level was higher in the hCG/hMG group.Other parameters did not exhibit a statistical difference.Conclusions:The hCG/hMG regimen is feasible and effective for treating male adolescents with CHH.The initial 3 months of treatment may be a window to optimally observe the strongest effects of therapy.Furthermore,results from the extended time-period showed positive outcomes at the 1-year mark;however,the long-term effectiveness,strengths,and weaknesses of the hCG/hMG regimen require further research.Trial Registration:ClinicalTrials.gov,NCT02880280;https://clinicaltrials.gov/ct2/show/NCT02880280.

Effect of Guizhi Fuling Pill combined with GnRH analog on cell proliferation and invasion as well as MEK/ERK pathway in endometriosis lesions

Objective: To study the effect of Guizhi Fuling Pill combined with gonadotropin-releasing hormone analog (GnRH-a) on cell proliferation and invasion as well as MEK/ERK pathway in endometriosis lesions. Methods: Patients who were diagnosed with endometriosis in Bazhong Hospital of Traditional Chinese Medicine between November 2014 and March 2017 were selected as the research subjects and randomly divided into two groups, observation group received preoperative Guizhi Fuling Pill combined with GnRH analog therapy, and control group received preoperative GnRH analog monotherapy. After surgical resection, the endometriosis lesion was collected to determine the mRNA expression of proliferation and invasion-related genes as well as the protein expression of MEK/ERK pathway molecules. Results: Id-1, Sema3A, c-IAP1, OPN and uPA mRNA expression as well as p-MEK, p-EKR1/2, caspase-3 and MMP2 protein expression in endometriosis lesion of observation group were significantly lower than those of control group while Bak, Smac, PAI-1, TIMP1 and TIMP2 mRNA expression as well as caspase-3 protein expression were significantly higher than those of control group. Conclusion: Guizhi Fuling Pill combined with GnRH analog can inhibit the cell proliferation and invasion as well as the MEK/ERK pathway activation in endometriosis lesions.

国产黄体生成素释放激素─A治疗子宫内膜异位症的临床研究

应用不同剂量（１００μｇ／ｄ，２００μｇ／ｄ）的国产黄体生成素释放激素－Ａ（ＬＨＲＨ－Ａ）治疗子宫内膜异位症６６例，其中Ⅰ期９例，Ⅱ期４７例，Ⅲ期１０例。合并不孕症２９例，子宫肌腺症１０例。结果表明，５００μｇ／ｄ组对卵巢内膜囊肿的疗效最佳，但对子宫腺肌症的效果不明显，停药后妊娠７例，占２４％（７／２９）。所用ＬＨＲＨ－Ａ的３种剂量均抑制Ｅ２，Ｐ，ＰＲＬ的分泌，使血中生殖激素下降，排卵抑制和卵巢内膜囊肿缩小，对血胆固醇有升高作用，临床主客观症状体征以５００μｇ／ｄ组变化最为明显。

Targeted therapy in advanced metastatic colorectal cancer: Current concepts and perspectives

The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor(VEGF)and epidermal growth factor receptor(EGFR)signaling has improved clinical outcome of patients withmetastatic colorectal cancer(mCRC).In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC.The effects of available treatment strategies for mCRC are often temporary,with resistance and disease progression developing in most patients.Thus,new treatment strategies are urgently needed.Some GI peptides including gastrin and gastrin releasing peptide,certain growth factors such as insulin-like growth factor-ⅠandⅡand neuropeptides such as growth hormone releasing hormone(GHRH)are implicated in the growth of CRC.Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide,GHRH,and with cytotoxic peptides that can be targeted to peptide receptors on tumors,are summarized in the second part of the review.

X-linked recessive Kallmann syndrome:A case report

BACKGROUND Kallmann syndrome(KS),also known as hypogonadotropic hypogonadism(HH)or olfactory-gonadal dysplasia,is a genetic condition in which the primary symptom is a failure to begin puberty or a failure to fully complete it.It occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility.The condition has a low prevalence that is estimated to be 1 in 4000 for male HH cases overall and 1:50000 for KS.It is three to five times more common in males than females.Whether this is a true sex imbalance or a reflection of how difficult KS/HH is to diagnose correctly in males vs females has yet to be fully established.CASE SUMMARY This article reports a 26-year-old male presenting with delayed puberty.The synthetic decapeptide luteinizing hormone-releasing hormone stimulation test showed that the secretion levels of follicle-stimulating hormone and luteinizing hormone were delayed.The eigengenes commonly associated with idiopathic HH(IHH)were screened,and an X-linked recessive(KAL-1)mutation was found.His gonadotropin and testosterone levels increased significantly after pulsatile gonadotropin-releasing hormone(GnRH)subcutaneous therapy by pump.A relevant literature review on the recent advances in the diagnosis and treatment of KS and genetic counseling was conducted.CONCLUSION KS is caused by a KAL-1 mutation that follows an X-linked recessive inheritance pattern.Pulsatile GnRH subcutaneous therapy by pump was effective in this patient.

Efficacy and Safety of Domestic Leuprorelin in Girls with Idiopathic Central Precocious Puberty： A Multicenter,Randomized, Parallel, Controlled Trial

Background：In central precocious puberty （CPP）,the pulse secretion and release ofgonadotropin-releasing hormone （GnRH） are increased due to early activation of the hypothalamic-pituitary-gonadal axis,resulting in developmental abnormalities with gonadal development and appearance of secondary sexual characteristics.The CPP without organic disease is known as idiopathic CPP （ICPP）.The objective of the study was to evaluate the clinical efficacy and safety of domestic leuprorelin （GnRH analog） in girls with ICPP.Methods：A total of 236 girls with ICPP diagnosed from April 2012 to January 2014 were selected and were randomized into two groups.One hundred fifty-seven girls in the test group were treated with domestic leuprorelin acetate,79 girls in the control group were treated with imported leuprorelin acetate.They all were treated and observed for 6 months.After 6-month treatment,the percentage of children with peak luteinizing hormone （LH） ≤3.3 U/L,the percentage of children with peak LH/peak follicle stimulating hormone （FSH） ratio 〈0.6,the improvements of secondary sexual characteristics,gonadal development and sex hormone levels,the change of growth rate of bone age （BA） and growth velocity,and drug adverse effects between two groups were compared.Results：After the treatment,the percentage of children with a suppressed LH response to GnRH,defined as a peak LH ≤3.3 U/L,at 6 months in test and control groups were 96.80% and 96.20%,respectively,and the percentage of children with peak LH/FSH ratio ≤0.6 at 6 months in test and control groups were 93.60% and 93.70%,respectively.The sizes of breast,uterus and ovary of children and the levels of estradiol （E2） were significantly reduced,and the growth rate of BA was also reduced.All the differences between pre-and post-treatment in each group were statistically significant （P 〈 0.05）,but the differences of the parameters between two groups were not significant （P 〉 0.05）.Conclusions：Domestic leuprorelin is effective and safe in the treatment of Chinese girls with ICPP.Its effectiveness and safety are comparable with imported leuprorelin.

小剂量米非司酮、LNG—IUS系统及GnRHa对子宫腺肌症的治疗观察

目的通过对240例不同治疗方法的子宫腺肌症患者临床资料的分析，观察小剂量米非司酮、左炔诺孕酮宫内缓释系统（LNG-IUS）及促性腺激素释放激素动剂（GnRHa）治疗的区别及各自的优势。方法筛选子宫腺肌症患者400例，随机抽取小剂量米非司酮治疗组80例、LNG—IUS治疗组80例及GnRHa治疗组80例。记录三种治疗方法对患者月经（经期、月经量）、痛经改变情况及对自身激素如雌激素、孕激素及丙氨酸氨基转移酶（ALT）改变情况，并进行统计学检验。结果三种治疗方法对月经的影响：小剂量米非司酮对经期影响较缓和，治疗经量过多，效果显著（P〈0．05）；LNG—IUS治疗中出现点滴出血，且出血时间长达3～6个月不等，出血量波动较大，总体效果与小剂量米非司酮治疗比较差异无统计学意义；GnRHa经期缩短明显，经量减少明显，治疗效果显著（P〈0．05）。三种治疗方法对痛经的影响：三组显效率比较差异有统计学意义，GnRHa显效率最高（P〈0．05）。LNG-IUS因有植入后点滴出血和环位的特异性，统计自觉痛经程度时患者表述不清，造成显效率可能下降，但总体显效率和有效率仍高于米非司酮治疗组。三种治疗方法对患者激素的影响：对患者雌激素的影响，三者影响中Gn—RHa影响最大（P〈0．05），小剂量米非司酮对雌激素影响较缓和，LNG—IUS影响最小。对患者孕激素的影响，三者均现出明显下降，经统计学检验，GnRHa较其他两者下降显著。对患者ALT的影响，可见三者都有明显的上升，但是GnRHa上升显著（P〈0．05），后经保肝治疗下降明显。结论小剂量米非司酮、LNG—IUS系统及GnRHa对子宫腺肌症治疗均有效，在治疗效果上LNG—IUS系统及GnRHa效果更佳；在普及中LNG—IUS系统及GnRHa又各有缺陷，如LNG-IUS系统的不良反应、GnRHa对肝功能的影响和必须反向添加治疗等，需要进一步合理用药。