Evidenzbasierte medikamentöse Therapieansätze der Infertilität

Evidence-based drug therapy for male infertility is often difficult because 30% of all cases of male infertility are classified as idiopathic, and another 30% need surgical treatment. Without knowledge of the underlying pathology, there is no foundation for a specific and causal treatment. Most of the currently used drug therapies are empirical at best; moreover, many of the studies on drug treatment for male infertility do not fulfill the required standards of evidence-based medicine (randomized, prospective, placebo-controlled), and the statistical endpoints used (sperm quality, pregnancy rate, baby take-home rate) are not uniform. This article, which is based on a literature survey and the current guidelines concerning drug therapy for male infertility, covers the most common treatment options. Regarding the currently insufficient scientific data for drug therapy and dietary supplements on male infertility, there is a demand for critical indications that take into consideration the possible side effects and the treatment costs. In the case of insufficient drug therapy for male infertility, reproductive medicine seems to be promising.     

Are antioxidants a viable treatment option for male infertility?

Oxidative stress is caused by an imbalance between ROS and antioxidants, which plays a significant role in the pathophysiology of many human diseases. There is extensive evidence highlighting the role of oxidative stress in male infertility due to elevated levels of sperm DNA fragmentation and abnormal semen parameters. The use of antioxidants is a potential therapeutic option to reduce ROS and improve semen quality. The appeal is that antioxidants can be easily obtained over the counter and are considered all-natural and therefore healthy. The hypothesis has been that by decreasing oxidative stress, antioxidants may be used for the treatment of male infertility. While initial studies of antioxidant supplementation suggested a beneficial role in the management of male subfertility, additional research has questioned the benefit of these therapies. The focus of this article is to present recent evidence assessing the viability of antioxidant therapy in the treatment of male infertility.     

Effect of adjuvant drug therapy after varicocelectomy on fertility outcome in males with varicocele‐associated infertility: Systematic review and meta‐analysis

Varicocele is one of the common correctable causes of male infertility. Recent studies have demonstrated varicocelectomy in males with abnormal semen parameters was associated with better fertility outcome, but the effect of adjuvant drug therapy after varicocelectomy on fertility outcome in patients with varicocele‐associated infertility remains undefined. Hence, the present meta‐analysis was performed to assess the efficacy of adjuvant drug therapy after varicocelectomy. The protocol was registered with PROSPERO (No. CRD42018093749). Ten randomised controlled trails containing 533 patients with adjuvant drug therapy after varicocelectomy and 368 patients with no medical treatment after varicocelectomy were included. Our analysis revealed that the improvement in pregnancy rate after adjuvant drug therapy was insignificant. (OR = 1.70, 95%CI = 0.99–2.91), but resulted in significant improvements in sperm concentration (MD = 13.71, 95%CI = 5.80–21.63) and motility (MD = 4.77, 95%CI = 3.98–5.56) at 3 months, sperm DNA integrity (SMD = 3.13, 95%CI = 1.50–4.75) and serum FSH level (MD = ?1.02, 95%CI = ?1.79 to ‐0.24). Therefore, compared to no medical treatment, the adjuvant drug therapy, especially the use of antioxidants seems to be associated with better fertility outcome. However, more evidences with high‐quality studies are necessary to conform its benefits.     

The pathophysiology of varicocele-associated male infertility

Varicocele is the most commonly identifiable, surgically correctable lesion associated with male-factor infertility. Surgical correction of a varicocele, whether unilateral or bilateral, results in improvement not only in semen parameters but also in spontaneous and assisted pregnancy rates. Varicoceles seem to induce a number of changes in the testicular microenvironment. These alterations in temperature, hemodynamics, and reactive oxidative species and antioxidant concentrations have been demon-strated to produce deleterious effects on spermatogenesis. However, despite current knowledge in the patho-physiology of varicocele-associated male infertility, the exact mechanism—or mechanisms—by which varicoceles impair fertility remains elusive. This review examines scientific evidence regarding the pathophysiology of varicocele-associated male infertility.     

Undescended testis and infertility—Is hormonal therapy indicated?

Purpose

The purpose of this chapter is to review hormonal therapy in cryptorchidism in boys to improve fertility.

Methods

Multiple searches, primarily in PubMed, were performed using various combinations of the terms: cryptorchidism, undescended testis (UDT), hormonal therapy, fertility, infertility, germ cell numbers, spermatogonia and semen analyses. In additions the pertinent articles from the reference lists in these papers were also obtained and reviewed.

Results

Data on fertility in unilateral cryptorchidism does not reveal a significant risk for infertility. Testes biopsies in childhood do not correlate with fertility parameters in adulthood. In bilateral cryptorchidism there is a significant risk of infertility. Results of hormonal treatment were not reported separately for bilateral cryptorchidism. Current data is insufficient to know if hormonal therapy is efficacious in bilateral UDT.

Conclusions

Hormonal therapy should not be used in childhood to improve fertility in cases of unilateral cryptorchidism. Testes biopsies in childhood to identify those at risk for infertility should not be performed in unilateral cryptorchidism. More data are needed to answer whether hormonal therapy is beneficial in bilateral UDT. There is insufficient data to establish that testis biopsies are helpful in bilateral cryptorchidism in identifying the subgroup with risk for infertility. They should not be performed in the routine clinical setting but may have a role in a research protocol.     

Seminal mast cells in infertile asthenozoospermic males

This work aimed to assess the possible association between the presence of seminal mast cells and asthenozoospermia. One hundred and seventy-six male subjects were investigated: group (Gr)1 (n=46) normozoospermic fertile controls, Gr2 (n=62) idiopathic asthenozoospermia, Gr3 (n=32) asthenozoospermia with scrotal varicocele and Gr4 (n=36) asthenozoospermia with leucocytospermia. Four smear slides were prepared for each semen sample to be stained with toluidine blue-pyronin to detect mast cells. A significant increase was shown in mast cell-positive samples among varicocele-associated and idiopathic asthenozoospermic patients in comparison with fertile controls. Seminal mast cells were also detected at higher frequency among smokers and in age group over 40 years. It is concluded that mast cells and their products may play a pivotal role in the pathogenesis of asthenozoospermia, possibly proposing a new goal for medical treatment of infertile males to pursue. In addition, this concept may in a way detain smoking as a cause of male infertility considering the clear abundance of mast cells in semen samples of smokers.     

CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population： a meta-analysis

Several studies have reported a relationship between the length of the CAG-repeat in the polymerase γ (POLG) gene and male infertility. However, other studies have not reproduced this result. In our study, the POLG-CAG-repeat length was analyzed in 535 healthy individuals from six Chinese Han populations living in different provinces. The frequencies of 10-CAG alleles and genotypes were high (97.38 and 94.13%, respectively), with no significant difference among the six Chinese Han populations. Furthermore, we determined the distribution of the POLG-CAG-repeat in 150 infertile men and 126 fertile men. Our study suggested that the distributions of POLG-CAG-repeat alleles and genotypes were not significantly different between infertile (95.67 and 92.67%, respectively) and fertile men (97.22 and 94.44%, respectively). In a subsequent meta-analysis, combining our data with data from previous studies, a comparison of the CAG-repeat alleles in fertile versus infertile men showed no obvious risk for male infertility associated with any particular allele (pooled odds ratio (OR)=0.94; 95% confidence interval (CI): 0.60-1.48). The significance level was not attained with any of the following genetic models: homozygote comparison (not 10/not 10 versus 10/10: OR=1.34; 95% CI: 0.66-2.72), heterozygote comparison (10/not 10 versus 10/10: OR=1.04; 95% CI: 0.78-1.38), dominant model comparison (not 10/not 10+10/not 10 versus 10/10: OR=1.08; 95% CI: 0.79-1.47) and recessive genetic comparison (not 10/not 10 versus 10/not 10+10/10: OR=1.31; 95% CI: 0.68-2.55). In conclusion, there is no significant difference of the frequencies of POLG-CAG-repeat variants among six Chinese Han populations, and this polymorphism may not be associated with Chinese male infertility. On the basis of a meta-analysis, there is no obvious association between CAG-repeat variants of the POLG gene and male infertility.     

Präoperative Dauertherapie

A large number of patients undergoing elective surgical procedures already take routine medication preoperatively. The majority of these patients use drugs for therapy of preexisting cardiovascular, pulmonary or endocrinological diseases which are independent of the planned surgical procedure. The number and type of preoperative drug therapy are correlated to age, gender and co-morbidity of the patients. Furthermore, patients with higher ASA-classes usually take more drugs, as they suffer from several medical diseases. Information about the perioperative handling of routine drug therapy is important for the planning of anaesthesia and surgery. A close cooperation of all medical specialities involved is necessary, in particular when patients take anticoagulants or other substances which should be withdrawn or replaced. This review focuses on the handling of routine preoperative medication by the anaesthesiologist in the light of available literature.     

Medical therapy for spermatogenic failure

Medical treatment of men with primary spermatogenic failure remains largely ineffective in contrast to those with secondary testicular failure. Treatment has been attempted with a multitude of agents ranging from hormones to nutritional supplements (antioxidants). While some studies have demonstrated benefit to some treatments, no treatments have consistently demonstrated efficacy nor has it been possible to reliably identify patients likely to benefit. Idiopathic spermatogenic failure likely results from multiple discrete defects in sperm production that are as yet unidentified. A better understanding of these defects will yield more effective treatment options and appropriate triage of patients to specific therapeutic regimens. This review focuses on the rationale and current evidence for hormonal and antioxidant therapy in medical treatment of male infertility, spermatogenic failure in particular. Although empiric medical therapy for spermatogenic failure has been largely replaced by assisted reproductive techniques, both treatment modalities could play a role, perhaps as combination therapy.     

【原创论文】应关注男性不育的药物治疗——睾酮：用还是不用？

在男性不育的治疗中是否使用睾酮是一个重要问题。2013年欧洲泌尿外科学会（EAU）在其最新版的男性不育治疗指南中明确指出“睾酮替代治疗是男性不育治疗的严格禁忌证”,这个论断引起了广泛的关注和争议。尽管目前还缺乏设计良好的临床对照研究来提供足够证据支持男性不育症的药物治疗,用来证明这些药物的有效性的研究机会不能被剥夺,药物治疗的研究应该被鼓励和加强（而不是简单地禁止）。无论从基本的医学原则、医学发展、医学专业知识方面,以及人文医学角度,包括睾酮在内的药物治疗都应该作为一线的治疗方法或基础治疗。因此,我认为EAU指南中于注男性不育治疗严格禁忌使用睾酮的论断考虑有欠周全,使用睾酮治疗男性不育的主要理由在本文中进行了充分的讨论。     

Total antioxidant capacity—Relevance,methods and clinical implications

Oxidative stress is pre-empted by an adequate level of antioxidants, which scavenge oxidants when they are produced in excess by different sources, including leukocytes and immature spermatozoa. Enzymatic antioxidants, such as superoxide dismutase, catalase and glutathione peroxidase, and several non-enzymatic antioxidants (proteins, vitamins and minerals), working as oxidant scavengers and cofactors of enzymatic antioxidants have been identified in seminal plasma. The total antioxidant capacity (TAC) is a diagnostic test that can be utilised in the male infertility workup. TAC measures the amount of total antioxidants in seminal plasma. Therefore, it provides an assessment of the reductive potential in seminal plasma. Several studies have investigated the diagnostic application of TAC in various andrology conditions. There is substantial evidence in the literature to show that infertile patients have lower seminal TAC in comparison with fertile men. Moreover, there is a positive correlation between TAC and seminal parameters, such as sperm concentration, motility and morphology. Evaluation of TAC together with reactive oxygen species (ROS) and sperm DNA fragmentation index (DFI) may be beneficial in the diagnosis of male infertility.     

特发性男性不育的药物治疗

无明显病因的男性不育,称之为特发性男性不育。自从1992年发明卵细胞胞质内单精子注射(ICSI)治疗男性不育以来,对难治性男性不育取得突破性进展,但对每一男性不育个体选择治疗时,传统治疗方法应受到重视,药物作为传统方法还将是重要的治疗手段之一。本文就目前对男性不育的基本认识、药物治疗的特点、临床常用药物、疗效、评价及预后进行了综述。     

Treatment strategies for advanced renal cell carcinoma: A new paradigm for surgical treatment

The induction of targeted drugs for the treatment of metastatic renal cell carcinoma has changed the treatment strategy for systemic therapy. Surgical treatment for metastatic renal cell carcinoma should also be reconsidered in the light of the effect of targeted drugs. The clinical benefit of cytoreductive nephrectomy for cases of metastatic renal cell carcinoma was proved in randomized trials in the cytokine era. However, at present, there has not been level 1 evidence for this in the targeted therapy era. Patients with better performance status and without poor risk factors tend to benefit from cytoreductive nephrectomy. Two ongoing large‐scale randomized studies might shed light on this issue. One of the remarkable differences in the efficacy between cytokines and targeted drugs, particularly tyrosine kinase inhibitors, is the reduction in the size of the primary tumors by tyrosine kinase inhibitors, including sunitinib and axitinib. Initial experiences with targeted therapy suggest that the neoadjuvant setting of tyrosine kinase inhibitors could be a viable option when the primary tumor shows local invasion and/or is unresectable. The present study does not support the routine neoadjuvant use of sunitinib because of the possibility of disease progression during the neoadjuvant therapy, and modest response and benefit. Axitinib, in contrast, shows larger reduction in the size of the primary tumor and might be used in the near future. Another issue is the combination of targeted therapy with metastasectomy. There is a lack of evidence for improved prognosis resulting from the neoadjuvant setting of tyrosine kinase inhibitors followed by metastasectomy. Further studies are warranted to investigate this.     

Gender and recovery after general anesthesia combined with neuromuscular blocking drugs

Previous studies suggest that women recover faster from general anesthesia than men, but it is unclear whether this is a result of a gender effect or differences in the pattern of drug administration or type of surgery. We performed a subset analysis comparing recovery characteristics from general anesthesia combined with neuromuscular blocking drugs of female and male patients, at risk of awareness, enrolled in a large trial testing the effectiveness of bispectral index (BIS) monitoring. We used multivariate statistical methods to adjust for differences in baseline characteristics, duration and extent of surgery, and anesthetic drug administration in 1079 patients (584 male, 495 female). Female patients had higher BIS values than male patients despite similar amounts of anesthetic drug administration (time-averaged mean [sd] BIS: male 44.6 [7.1] versus female 46.4 [6.6]; P = 0.005). Time to eye opening after anesthesia and time to eligibility to discharge from the postanesthesia care unit were less in women than men (male 13.9 [13.2] min versus female 10.6 [11.6] min; P < 0.001; male 133 [209] min versus female 78 [106] min; P < 0.001, respectively). These differences persisted after multivariate adjustment (both P < or = 0.001). Gender has an independent effect on recovery times in patients undergoing general anesthesia combined with neuromuscular blocking drugs, with women recovering faster than men. Higher BIS values during maintenance of anesthesia in women, despite similar amounts of anesthetic drug administration, suggests that women are less sensitive to the hypnotic effect of anesthetic drugs than men and may help explain faster recovery times in women.     

Successful management of infertility due to retrograde ejaculation using assisted reproductive technologies: a report of two cases

Although retrograde ejaculation is a relatively uncommon cause of infertility, it is nonetheless the most common cause of ejaculatory dysfunction. Retrograde ejaculation is characterized by either all or part of the seminal fluid going into the bladder. The initial management of patients with ejaculatory dysfunction is medical therapy. In couples who have failed medical therapy, assisted reproductive techniques using sperm harvested from either the urine or the male reproductive tract would be the ultimate option. We report successful management of two couples, both men with advanced age and complete retrograde ejaculation, by intrauterine insemination in one and in vitro fertilization (IVF) using intracytoplasmic sperm injection (ICSI) in the other using sperm harvested from urine. The cases reported herein suggest that male infertility due to retrograde ejaculation may be successfully treated in men significantly older than the usual reproductive age and that traditional methods of hydration and urine alkalinization allow for the successful recovery of fertile sperm for ART. The selection of the method of ART must be individualized to the needs of each couple based upon both male and female factors.     

Renal vascular disease: medical management, angioplasty, and stenting

In the absence of large, prospective, quality randomized trials, there remains tremendous debate concerning the optimal management of patients with renal vascular disease. This debate is compounded by the fact these patients do not represent a homogeneous group; different causes and presentations each carry a different prognosis and potential response to therapy. Therapeutic options include medical management, surgery, or percutaneous approaches (angioplasty or stenting). This review examines the results of observational studies of medical and percutaneous therapies for blood pressure control and preservation of renal function. Generally, in patients with fibromuscular disease, the results of percutaneous management are superior to medical therapy. Although these observational studies are difficult to compare, in patients with atheromatous disease, the results with interventional and medical therapy appear roughly similar. There have been three randomized prospective trials of routine angioplasty versus medical management. These trials show little advantage to interventional therapies in those patients whose blood pressure is well controlled with medication who do not show progression of renal insufficiency during medical management. Based on these data, this review outlines a potential management strategy that relies on an individualized risk benefit assessment.     

Psychology of male infertility — a literature survey

Fifty-three articles on the psychology of male infertility published between 1948 and 1985 are reviewed with respect to theoretical backgrounds, methodological approaches and results suggesting an influence of psychological factors on male fertility. Although the data of most empirical studies are found to be incomplete and inconclusive because of conceptual deficiencies and insufficient methods, there is some evidence for stress responses negatively affecting male fertility. The variety of psychological factors presented in the literature indicates the heterogeneity of psychological involvement in male infertility. In conclusion, goals for future research on psychobiological aspects of male infertility are suggested and methodological criteria are outlined.     

Systemic Therapy for Penile Cancer

Penile squamous cell carcinoma (PSCC) is a very rare disease and its prognosis primarily depends on regional lymph node involvement. Although a cure can be obtained in patients with a low metastatic burden using surgery as standalone option, combined modality therapy is required for more advanced cases. In patients with multiple fixed or bulky inguinal lymph nodes, and in those with enlarged pelvic lymph nodes, chemotherapy is moderately effective, with an objective response rate of approximately 50% if a triple regimen of cisplatin, taxane, and ifosfamide or 5-fluorouracil is used. However, long-term survival rates are dismal irrespective of the possibility of administering the most effective treatments, and new drugs are warranted. Therefore, huge unmet medical needs remain in the management of patients with advanced disease. Among the limitations is the optimal timing of chemotherapy delivery in relation to lymphadenectomy. Targeted therapies against the EGFR pathway provided the most promising results in patients after chemotherapy failure. The next research efforts should focus on combining new drugs with standard therapy options, and on identification of biomarkers of clinical benefit and new prognostic factors to help physicians in orienting therapeutic strategies.     

Medical versus surgical androgen suppression therapy for prostate cancer: a 10-year longitudinal cost study

PURPOSE: We provide a relative cost comparison of medical versus surgical androgen suppressive therapy for prostate cancer. MATERIALS AND METHODS: Comparison is based on a cohort of 96 patients who began androgen suppressive therapy for prostate cancer between 1988 and 1990. Patients were followed until death or the end point of study in June 2000 at which time 15% were alive. Current Medicare orchiectomy reimbursements were compared to 1999 wholesale drug costs. RESULTS: For an individual patient the cost of luteinizing hormone releasing hormone (LH-RH) agonist treatment surpassed the cost of surgery at less than 4.2 to 5.3 months, and for combined androgen blockade (LH-RH agonists and nonsteroidal antiandrogens) at less than 2.7 to 3.4 months. For 5 (5.2%) patients on combined androgen blockade and 6 (6.3%) on LH-RH agonists alone, medical therapy would have had a cost advantage over bilateral orchiectomy. For the androgen suppression cohort the cost of LH-RH agonist treatment was 10.7 to 13.5 times and combined androgen blockade was 17.3 to 20.9 times the cost of bilateral orchiectomy. Urology resource use comparisons are provided. These findings significantly underestimate the cost advantage of surgery. A seventh of the patients were alive at study end point, and prostate specific antigen induced stage shifting and changes in practice patterns resulted in earlier and more frequent androgen suppressive treatment. CONCLUSIONS: Except for patients with short anticipated survivals current medical androgen suppressive treatment options are more costly than bilateral orchiectomy. There is a need for a cost comparable medical option to orchiectomy.     

耳穴贴压在肩袖损伤住院患者关节镜术后早期疼痛管理中的应用

目的探讨耳穴贴压在肩袖损伤住院患者关节镜术后早期疼痛管理中的应用效果。 方法选取2018年1月至2019年10月在北京大学人民医院创伤骨科行肩关节镜治疗的肩袖损伤患者共84例,对照组42例采取常规镇痛措施;观察组42例在常规镇痛的基础上于入院后给予患者进行耳穴贴压。采用视觉模拟评分法（visual analogue scale,VAS）评估两组患者术后24 ~ 72 h的疼痛改善情况。 结果观察组术后48 h的静息VAS评分和活动VAS评分较术后24 h的VAS评分改善均优于对照组,差异均有统计学意义（P<0.05）;观察组术后72 h的静息VAS评分和活动VAS评分较术后24 h的VAS评分改善均优于对照组,差异均有统计学意义（P<0.05）。 结论中医耳穴贴压能有效辅助减轻肩袖损伤住院患者关节镜术后的早期疼痛,操作简便,值得在临床推广。