今日の臨床サポート

男性不妊

著者: 谷口久哲 関西医科大学腎泌尿器外科学講座

監修: 松田公志 関西医科大学 泌尿器科学教室

著者校正/監修レビュー済:2022/07/06
参考ガイドライン:
  1. 日本生殖医学会生殖医療ガイドライン
  1. 日本生殖医学会生殖医療の必須知識2020
  1. WHO Laboratory Manual for the Examination and Processing of Human Semen, sixth edition. 2021
患者向け説明資料

概要・推奨   

  1. 特発性精子形成障害に対して、精子濃度や運動率を改善することが強いエビデンスとして証明された治療法はない。
  1. 精巣機能障害による非閉塞性無精子症でも、精巣内では部分的に精子が作られている場合の多いことが知られてきた。いわゆるmicro-TESE(顕微鏡下精巣内精子採取術)で、非閉塞性無精子症の30~40%で精子を採取することができる(推奨度1)
  1. 閉塞性無精子症に対しては、閉塞部位によって精管精管吻合術や精巣上体精管吻合術、あるいは射精管開放術などの精路再建術が行われ、40%以上の高い確率で自然妊娠が成立する(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
谷口久哲 : 未申告[2022年]
監修:松田公志 : 講演料(アステラス製薬株式会社),奨学(奨励)寄付など(小野薬品工業株式会社)[2022年]

改訂のポイント:
  1. 2022年4月から精巣内精子採取術・Y染色体微小欠失検査・勃起不全による男性不妊治療に用いるPDE5阻害剤が保険適用となった。
  1. 2021年、WHOによる精液検査の基準値が改訂された。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 1排卵周期に妊娠する確率は15%、1年後に挙児を得られないのは15%になる。挙児を希望するカップルの、およそ8組に1組が不妊とされる。不妊症カップルで男性側に何らかの原因があるのは約半数で、そのうち半数は女性側にも異常が指摘される[1]
  1. 男性不妊症の原因には、精子形成障害、通過障害などの精路の異常、勃起射精障害などの性機能障害がある。多数を占める精子形成障害は、原因不明のことが多い。各種検査で異常を認めないが妊娠を得られないカップルも少なくない。
  1. 男性不妊症の診療では、女性側の年齢、妊孕力を考慮して検査、治療を選択しなければならない。
  1. 不妊症診療においては、カップルの人生観が診療に大きな影響を与える。検査や治療の選択は、十分なインフォームドコンセント(IC)に基づいた、カップルの自己決定による。
 
  1. Y染色体長腕上にAZFと呼ばれる精子形成に関わる遺伝子群が存在することが明らかになっており、この微小欠失によって精子形成障害が生じる[2]。一部の遺伝子は欠失の有無を検索できる。AZFa,AZFbの欠失では、micro-TESEでも精子を発見することはできない(推奨度3O)
  1. Y染色体長腕には、精子形成に関わる遺伝子群が存在し、それらはAZFa、AZFb、AZFcの3領域に分けられている。
  1. 同じ遺伝子が核酸配列を逆にして複数個繰り返すパリンドロームと呼ばれる複雑な構造をなしており、欠失はいくつかのタイプに分けることができる。
  1. AZFa、AZFb領域が欠失している場合は精巣内でも精子形成が認められないことが明らかになっており、micro-TESEの適応の診断に有用である。
  1. 精巣内精子採取術の適応の判断を目的として実施した場合、Y染色体微小欠失検査は保険診療で可能である。(2022年4月~)
 
  1. 男性が染色体異常や遺伝子異常を持つ場合、子供に同じような異常が生じる可能性がある。実際には、精巣内で精子が認められ、妊娠、挙児が得られた場合の子供の異常の頻度は高くないが、治療前に遺伝カウンセリングが必要である(推奨度2O)
  1. Klinefelter症候群で精巣内に精子が認められた場合、精子の遺伝子構成は正常(23,Xまたは23,Y)が大多数を占め、24XXなどの異常は数%程度と報告されている[3]
  1. 生まれた子供についても、性染色体異常のないことが多い。
  1. 常染色体転座では、精子の染色体構成は転座の種類や切断点によって異なるが、常染色体のトリソミーやモノソミーは生存できないことが多く、出生した子供での異常頻度は高くない。
  1. Y染色体の遺伝子の微小欠失は、男児が生まれれば伝播する。
 
  1. 射精障害に対する薬剤としては、近年第2世代の三環系抗うつ薬であるアモキサピンが用いられることが多くなり、第1世代の三環系抗うつ薬であるイミプラミンの使用は減っている。逆行性射精に対しては有効率が高いが、全く精液が出ないanejaculationへの有効性は低い[4]。近年はアモキサンが有効との報告も多い[5]。射精障害(射精困難)はときに治療に難渋することがあり、挙児のためには人工授精などの補助生殖技術が必要なこともある(推奨度2O)
  1. 射精障害には、後腹膜リンパ節郭清術、脊損、糖尿病などによる逆行性射精、精液が全く出ないanejaculationのほかに、強い刺激がないと射精できない腟内射精障害がある。
  1. 治療には、前立腺精嚢の経直腸的マッサージ、射精後尿採取などによる精子回収のほかに、三環系抗うつ薬などの交感神経刺激作用のある薬剤が奏功する可能性がある[6]
  1. 適応外使用であるが、アモキサピンの使用が逆行性射精に対して診療報酬審査で認められている。
  1. 用法・用量:「アモキサピン1日量25~50mgを1日1回夕食後、あるいは眠前に連日服用する。効果不十分の場合には、1日量75mgまで増量する。また用時服用では1回量25~50mgを1時間前に1回服用する」。
  1. 腟内射精障害には、異常なマスターベーションなどの習慣が射精障害の原因となっている場合もある。
  1. 早漏に対しては、SSRIが有効であるが、わが国では保険適用ではない。
 
  1. 勃起障害に対する治療は原因によって異なるが、不妊症で多い心因性のものにはカウンセリングや勃起補助薬(ホスホジエステラーゼ5(PDE5)阻害薬)が有用である[7](推奨度2O)
  1. 本邦における男性不妊の原因で、性機能障害が占める割合は13.5%であり[8]、膣内射精障害が多い[9]
  1. 勃起障害の原因検索には、夜間睡眠時勃起現象の有無の確認、陰茎内プロスタグランジンE投与による勃起発現の有無による血管性勃起障害の診断などが行われる。
  1. PDE5阻害剤は、勃起障害を伴う男性不妊症に対して有効である。(2022年4月~保険適用)
 
  1. 処方例:
  1. 器質的疾患が除外できる勃起障害に対しては、下記の1)2)のいずれかを処方する。亜硝酸薬との併用は絶対禁忌である。
  1. 1) シアリス錠10mg、20mg 1錠 分1 性交1時間前 [㊜勃起不全]
  1. 2) バイアグラ錠25mg、50mg 1錠 分1 性交1時間前 [㊜勃起不全]
 
問診・診察のポイント  
  1. 挙児を希望して1年以上妊娠が得られない場合、不妊症として検査を行う[10]
  1. 男性への問診は、以下のポイントを押さえる。

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文献 

A Kamischke, E Nieschlag
Update on medical treatment of ejaculatory disorders.
Int J Androl. 2002 Dec;25(6):333-44.
Abstract/Text Among the treatment modalities for ejaculatory disorders pharmacological treatment is the least invasive option. In this review, medical treatments for retrograde ejaculation (RE) and anejaculation (AE) are discussed systematically. Thirty-six studies dealing with patients with RE and 40 with AE evaluated the use of medical treatment and were included in this review. In addition four articles dealing with prostatic massage in anejaculatory patients were considered. Sperm quality in patients with retrograde and AE is often impaired. In patients with RE no differences in response to medical treatment could be detected between the different underlying diagnoses. Compared with ephedrine, imipramine and chlorpheniramine + phenylpropanalamine showed significantly higher reversal rates, while differences between the other treatments were not significant. Regarding the reversal of AE, the alpha agonistic drugs were significantly inferior to treatment with parasympathetic drugs. Of the different alpha agonistic medical treatments for the reversal of AE, milodrin showed significantly better rates than imipramine (p = 0.008), pseudoephidrine (p = 0.02) and ephedrine (p = 0.044), while all other treatments were not significantly different (p = 0.4). In conclusion, medical treatment for reversal of RE offers a realistic chance of conceiving offspring naturally and should be the treatment modality of first choice. In contrast, in AE, medical treatment cannot be recommended generally as treatment of first choice as it shows low overall success rates compared with electrovibration stimulation and electroejaculation. Under consideration of the mostly uncontrolled design of the majority of studies published, controlled clinical trials comparing different treatment options appear urgently warranted.

PMID 12406365
Stephen Boorjian, Carin V Hopps, Sameh W Ghaly, Marilyn Parker, John P Mulhall
The utility of sildenafil citrate for infertile men with sexual dysfunction: a pilot study.
BJU Int. 2007 Sep;100(3):603-6. doi: 10.1111/j.1464-410X.2007.07038.x. Epub 2007 Jul 21.
Abstract/Text OBJECTIVE: To investigate the use the sildenafil citrate, recognized as a first-line therapy for men with erectile dysfunction (ED), and which is safe and effective in men with various causes and severity of ED, including psychogenic ED, in a population of infertile men with sexual dysfunction.
PATIENTS AND METHODS: Infertility is a major source of life stress and might be associated with sexual dysfunction through the erosion of self-esteem and self-confidence, and in stimulating discord in a relationship. Men presenting for evaluation of fertility who on questioning by the physician reported the recent onset of sexual dysfunction, had a history taken, a physical examination, hormonal profile, and completed the International Index of Erectile Function (IIEF), a validated inventory for assessing sexual dysfunction. Thirty men with a score of <26 on the erectile function domain of the IIEF, or who complained of new onset rapid or delayed ejaculation, were treated with sildenafil with no randomization or placebo control. The evaluation was repeated and the IIEF completed again > or =3 months after starting treatment.
RESULTS: For men complaining of ED, subjective erectile rigidity, duration of erection, and the percentage of successful penetration attempts significantly improved with sildenafil. The mean (sd) IIEF domain scores for erection and satisfaction, at 18 (4) vs 27 (3), and 12 (2) vs 16 (3) (both P = 0.01), and orgasm, at 4 (1) vs 6 (3) (P = 0.001), respectively, significantly improved after treatment. In patients with ejaculatory dysfunction, the function improved in 64% after sildenafil therapy.
CONCLUSIONS: We identified the nature of sexual dysfunction associated with male-factor infertility, and showed the efficacy of sildenafil therapy in men with this condition.

PMID 17590181
Yasushi Yumura, Akira Tsujimura, Takashi Imamoto, Yukihiro Umemoto, Hideyuki Kobayashi, Koji Shiraishi, Takeshi Shin, Hisanori Taniguchi, Koji Chiba, Yasushi Miyagawa, Teruaki Iwamoto
Nationwide survey of urological specialists regarding male infertility: results from a 2015 questionnaire in Japan.
Reprod Med Biol. 2018 Jan;17(1):44-51. doi: 10.1002/rmb2.12065. Epub 2017 Oct 4.
Abstract/Text Purpose: To investigate the incidence, etiology, treatment indications, and outcomes regarding infertile male patients in Japan.
Methods: Between April, 2014 and March, 2015, the authors contacted 47 clinical specialists in male infertility who had been certified by the Japan Society for Reproductive Medicine. The participating clinicians were sent a questionnaire regarding information on their infertile patients, according to etiology and the number and success rates of male infertility operations that had been performed in their practice.
Results: Thirty-nine specialists returned the questionnaire and provided information regarding 7268 patients. The etiology of infertility included testicular factors, sexual disorders, and seminal tract obstruction. During the study year, the clinicians performed varicocelectomies, testicular sperm extractions (TESEs), and re-anastomoses of the seminal tract. The rate of successful varicocelectomies was >70%. The sperm retrieval rates with conventional TESE and microdissection TESE were 98.3% and 34.0%, respectively, while the patency rates with vasovasostomy and epididymovasostomy were 81.8% and 61.0%, respectively.
Conclusion: Surgical outcomes for infertile male patients are favorable and can be of great clinical benefit for infertile couples. To achieve this, urologists should work in collaboration with gynecological specialists in order to optimize the treatment of both partners.

PMID 29371820
Marcelo Vieira
Microdissection is the best way to perform sperm retrieval in men with non-obstructive azoospermy? | Opinion: No, there are other options.
Int Braz J Urol. 2018 Nov-Dec;44(6):1067-1070. doi: 10.1590/S1677-5538.IBJU.2018.06.03.
Abstract/Text
PMID 30516926
Gloria J McVay, David J Cooke
Beyond budgeting in an IDS: the Park Nicollet experience.
Healthc Financ Manage. 2006 Oct;60(10):100-2, 104, 106 passim.
Abstract/Text Beyond budgeting transcends the limitations of traditional budgeting by replacing fixed financial targets with targets based on key performance indicators. For Park Nicollet Health Services, the decision to implement beyond budgeting coincided with a larger move to adopt a Lean approach to management. Park Nicollet's process to implement beyond budgeting-from submission of the initial proposal through two test runs with process refinements to full implementation-lasted about one year, from January 2005 to January 2006.

PMID 17040037
T Matsuda, M Nonomura, K Okada, K Hayashi, O Yoshida
Cytogenetic survey of subfertile males in Japan.
Urol Int. 1989;44(4):194-7.
Abstract/Text Chromosomal analysis of 554 consecutive Japanese male patients attending a subfertility clinic revealed 18 (3.2%) major chromosomal aberrations. The incidence of sex chromosomal anomalies and autosomal anomalies is 1.3 and 2.0%, respectively, which is significantly higher than that for the general population. All 7 sex chromosomal anomalies were found among the azoo- or oligozoospermic patients, while the incidence of autosomal anomalies for the normozoospermic patients was statistically similar to that for the azoo- or oligozoospermic patients. Therefore, cytogenetic analysis is recommended not only for patients with reduced sperm density but also for subfertile patients with normozoospermia.

PMID 2800053
Jonathan D Schiff, Gianpiero D Palermo, Lucinda L Veeck, Marc Goldstein, Zev Rosenwaks, Peter N Schlegel
Success of testicular sperm extraction [corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome.
J Clin Endocrinol Metab. 2005 Nov;90(11):6263-7. doi: 10.1210/jc.2004-2322. Epub 2005 Aug 30.
Abstract/Text PURPOSE: The aim of this study was to report the successful fertility treatment of men with Klinefelter syndrome using testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI).
METHODS: A total of 42 men with Klinefelter syndrome who underwent 54 TESE procedures were identified. Before TESE, patients with serum testosterone levels less than 15.6 nmol/liter were treated with an aromatase inhibitor. Sperm retrieval rates and results of ICSI, including fertilization and clinical pregnancy, were collected.
RESULTS: Mean pretreatment FSH and testosterone levels were 33.2 IU/liter and 9.8 nmol/liter. During medical therapy, the mean testosterone level rose to 17.0 nmol/liter (P < 0.01). Spermatozoa were found during 39 microdissection TESE procedures, on the day before, or day of oocyte retrieval during a programmed in vitro fertilization cycle. The sperm retrieval rate was 72% (39 of 54) per TESE attempt, and 29 of the 42 different men (69%) had adequate sperm found for ICSI. Thirty-three in vitro fertilization cycles yielded embryos for transfer in the 39 (85%) cycles with sperm retrieved. Eighteen clinical pregnancies have resulted in 21 live births [18 of 39 (46%)]. All children had a normal karyotype.
CONCLUSION: TESE/ICSI is a successful intervention for the majority of patients with azoospermia and Klinefelter syndrome. Sperm retrieval and ICSI success in men with Klinefelter syndrome are comparable with other men with nonobstructive azoospermia treated at our center.

PMID 16131585
I Madgar, R Weissenberg, B Lunenfeld, A Karasik, B Goldwasser
Controlled trial of high spermatic vein ligation for varicocele in infertile men.
Fertil Steril. 1995 Jan;63(1):120-4.
Abstract/Text OBJECTIVE: To determine whether high ligation is an effective treatment for infertile men with clinical varicocele.
DESIGN: A randomized, controlled trial of high spermatic vein ligation was carried out. The patients were treated and observed for 3 years.
SETTING: Infertility treatment clinic and andrology laboratory in a hospital.
PATIENTS: Infertile men with abnormal semen analysis because of varicocele only.
INTERVENTION: High ligation 1 year postrecruitment (group A) and at the beginning of the study (group B).
RESULTS: Among the 20 couples in group A, 2 pregnancies (10%) were achieved within the 1st year of observation period. During the year after high ligation, there were 8 pregnancies (44.4%), and during the 2nd year after high ligation, there were 4 more pregnancies (22.2%). In group B, 15 pregnancies (60%) occurred within the 1st year after operation. Three pregnancies (12%) and 1 pregnancy (4%) occurred during the 2nd and 3rd year, respectively. After operation in all patients of both groups, there was significant improvement in semen parameters, regardless of pregnancy occurrence. The difference in pregnancy rate (PR) between the operated group B and nonoperated group A during the 1st year of study was found to be highly significant.
CONCLUSIONS: It is concluded that in a population of infertile men presenting varicocele as the only demonstrable factor of infertility, the varicocele is clearly associated with infertility and reduced testicular function, and its correction by ligation improves sperm parameters and fertility rate. Furthermore, the highest PR in both groups occurred during the 1st year postoperation.

PMID 7805900
Johannes L H Evers, John A Collins
Assessment of efficacy of varicocele repair for male subfertility: a systematic review.
Lancet. 2003 May 31;361(9372):1849-52. doi: 10.1016/S0140-6736(03)13503-9.
Abstract/Text BACKGROUND: Varicocele repair is a widely used treatment for subfertility. Our aim was to identify and combine the results from randomised controlled trials published to ascertain whether the pregnancy rates after varicocele repair are higher than those with no treatment.
METHODS: We did a systematic review of seven studies identified by searching Medline and a register of controlled trials. We also searched the contents of specialist journals and the annual meeting programmes of relevant societies by hand. Inclusion criteria were treatment of varicocele in subfertile couples, random allocation to treatment and control groups, and pregnancy or livebirth rates as an outcome measure. We pooled data by use of fixed and random effects models.
FINDINGS: None of seven eligible studies published between 1979 and 2002 described a strategy for concealment of the allocation sequence. There were 61 pregnancies among 281 treated couples and 50 pregnancies among 259 controls. The overall relative benefit of treatment was 1.01 (95% CI 0.73-1.40) by the fixed effects model and 1.04 (0.62-1.75) by the random effects model. The overall risk difference was 0.2% (-7 to 7) and 3% (-7 to 14), respectively. In subgroup analyses, varicocele treatment was not effective in trials restricted to male subfertility with clinical varicocele, or in those that included men with subclinical varicocele or normal semen analysis. However, this systematic review, done with a meta-analytical method, might have had insufficient power to detect small effects because of the small number of patients in some subgroups.
INTERPRETATION: Varicocele repair does not seem to be an effective treatment for male or unexplained subfertility.

PMID 12788571
Joel L Marmar, Ashok Agarwal, Sushil Prabakaran, Rishi Agarwal, Robert A Short, Susan Benoff, Anthony J Thomas
Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis.
Fertil Steril. 2007 Sep;88(3):639-48. doi: 10.1016/j.fertnstert.2006.12.008. Epub 2007 Apr 16.
Abstract/Text OBJECTIVE: To determine the efficacy of varicocelectomy as a treatment for male factor infertility by improving the chance of spontaneous pregnancy.
DESIGN: Meta-analysis.
SETTING: Cleveland Clinic's Glickman Urological Institute.
PATIENT(S): Infertile men with abnormal results on semen analyses and a palpable varicocele.
INTERVENTION(S): Surgical varicocelectomy.
MAIN OUTCOME MEASURE(S): Spontaneous pregnancy outcome.
RESULT(S): The odds of spontaneous pregnancy after surgical varicocelectomy, compared with no or medical treatment for palpable varicocele, were 2.87 (95% confidence interval [CI], 1.33-6.20) with use of a random-effects model or 2.63 (95% CI, 1.60-4.33) with use of a fixed-effects model. The number needed to treat was 5.7 (95% CI, 4.4-9.5).
CONCLUSION(S): Surgical varicocelectomy in infertile men with palpable lesions and at least one abnormal semen parameter improves the odds of spontaneous pregnancy in their female partners. Five studies were included (two randomized, three observational). All were scored for bias. Our study suggests that varicocelectomy in selected patients does indeed have beneficial effects on fertility status.

PMID 17434508
Abdulaziz Baazeem, Eric Belzile, Antonio Ciampi, Gert Dohle, Keith Jarvi, Andrea Salonia, Wolfgang Weidner, Armand Zini
Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair.
Eur Urol. 2011 Oct;60(4):796-808. doi: 10.1016/j.eururo.2011.06.018. Epub 2011 Jul 5.
Abstract/Text CONTEXT: Varicocele is a common condition, found in many men who present for infertility evaluation.
OBJECTIVE: To assess the effect of varicocelectomy on male infertility.
EVIDENCE ACQUISITION: A literature search was performed using Embase and Medline. Literature reviewed included meta-analyses and randomized and nonrandomized prospective (controlled and noncontrolled) studies. In addition, a new meta-analysis was performed.
EVIDENCE SYNTHESIS: Four randomized controlled trials reporting on pregnancy outcome after repair of clinical varicoceles in oligozoospermic men were identified. Using the random effect model, the combined odds ratio was 2.23 (95% confidence interval [CI], 0.86-5.78; p=0.091), indicating that varicocelectomy is moderately superior to observation, but the effect is not statistically significant. We identified 22, 17, and 5 prospective studies reporting on sperm concentration, total motility, and progressive motility, respectively, before and after repair of clinical varicocele. The random effect model combined improvement in sperm concentration was 12.32 million sperm per milliliter (95% CI, 9.45-15.19; p<0.0001). The random effect model combined improvement in sperm total and progressive motility were 10.86% (95% CI, 7.07-14.65; p<0.0001) and 9.69% (95% CI, 4.86-14.52; p=0.003), respectively. These results indicate that varicocelectomy is associated with a significant increase in sperm concentration as well as total and progressive motility. Prospective studies also show that varicocelectomy reduces seminal oxidative stress and sperm DNA damage as well as improving sperm ultramorphology. Studies indicate that a microsurgical approach to a varicocele repair results in less recurrence and fewer complications than other techniques.
CONCLUSIONS: Although there is no conclusive evidence that a varicocele repair improves spontaneous pregnancy rates, varicocelectomy improves sperm parameters (count and total and progressive motility), reduces sperm DNA damage and seminal oxidative stress, and improves sperm ultramorphology. The various methods of repair are all viable options, but microsurgical repair seems to be associated with better outcomes.

Copyright © 2011. Published by Elsevier B.V.
PMID 21733620
Renbin Yuan, Hui Zhuo, Dehong Cao, Qiang Wei
Efficacy and safety of varicocelectomies: A meta-analysis.
Syst Biol Reprod Med. 2017 Apr;63(2):120-129. doi: 10.1080/19396368.2016.1265161. Epub 2017 Feb 14.
Abstract/Text This study reviewed the efficacy and safety of the three surgical approaches for varicocele (microsurgical, laparoscopic, and open varicocelectomy). A systematic review of the relevant randomized clinical trials was performed. Trials were identified from specialized trials register of the Cochrane UGDP Group, the Cochrane library, additional electronic searches (mainly MEDLINE, EMBSAE, SCI, CBM), and handsearching. Clinical trials comparing microsurgical, laparoscopic and open varicocelectomies were included. Statistical analysis was managed using Review Manager 5.3. Seven clinical trials of 1,781 patients were included. The meta-analysis indicated that compared with open varicocelectomy, microsurgery had a higher pregnancy rate (p=0.002), while there was nonsignificant difference between microsurgical and laparoscopic varicocelectomies or between laparoscopic and open varicocelectomies. Both microsurgical and laparoscopic varicocelectomies had a greater increase in postoperative sperm concentration than open varicocelectomy (p=0.008 and p=0.001, respectively). Microsurgical varicocelectomy also showed better improvement in postoperative sperm motility (p=0.02). Compared with the other two, microsurgical varicocelectomy had the longest operative time (p=0.01 and p=0.0004 respectively). A nonsignificant difference was found in the hospital stay between the three approaches, whereas microsurgical and laparoscopic varicocelectomies had a shorter time to return to work. Moreover, microsurgical varicocelectomy had a lower incidence of postoperative complications and recurrence compared with the others. Analysis of current evidence shows that microsurgical varicocelectomy has a longer operative time, lower incidence of postoperative complications, and recurrence than laparoscopic and open varicocelectomies, and shows a higher pregnancy rate, with a greater increase in postoperative sperm concentration, better improvement in postoperative sperm motility, and shorter time to return to work than open varicocelectomy.

PMID 28301253
Hisanori Taniguchi, Teruaki Iwamoto, Tomohiko Ichikawa, Atsushi Nagai, Hiroshi Okada, Masato Fujisawa, Akira Tsujimura, Koji Shiraishi, Hatsuki Hibi, Koichi Nagao, Akira Iwasaki, Tomomi Kamba, Hiroshi Tomomasa, Shingo Takada, Tadashi Matsuda, Male Infertility Surgical Forum in Japan
Contemporary outcomes of seminal tract re-anastomoses for obstructive azoospermia: a nationwide Japanese survey.
Int J Urol. 2015 Feb;22(2):213-8. doi: 10.1111/iju.12631. Epub 2014 Sep 23.
Abstract/Text OBJECTIVES: To evaluate current outcomes of seminal tract re-anastomoses in Japan, and to compare them with historical data.
METHODS: A total of 213 patients with obstructive azoospermia who underwent seminal tract re-anastomosis from April 2008 to March 2012 at 25 institutions were enrolled in the present study. The outcomes of the procedure were compared with those reported in a previous multi-institutional study carried out in 2000.
RESULTS: The percentage of partners aged over 35 years was 37%. A microsurgical double-layer anastomosis was carried out 83.0% of the time. Sperm were observed in ejaculate postoperatively in 68.9% and 41.5% of patients who underwent a vasovasostomy or a vasoepididymostomy, respectively. Natural conception occurred in 27.5% of patients after a vasectomy and 32.3% of patients with an epididymal obstruction. Except for the ratio of natural conception in patients with vasal obstruction after herniorrhaphies, there were no significant differences in final ratios of sperm appearance and natural conception between the previously reported study and the present study.
CONCLUSIONS: Compared with historical data, contemporary seminal tract re-anastomosis in Japan seems to provide equivalent or better outcomes, depending on the cause of obstruction. Seminal tract re-anastomosis is a valid treatment option for patients with obstructive azoospermia.

© 2014 The Japanese Urological Association.
PMID 25252153
Colin M Howles, Toshiaki Tanaka, Tadashi Matsuda
Management of male hypogonadotrophic hypogonadism.
Endocr J. 2007 Apr;54(2):177-90. Epub 2007 Feb 8.
Abstract/Text
PMID 17287584
Abdelhamid M Attia, Ahmed M Abou-Setta, Hesham G Al-Inany
Gonadotrophins for idiopathic male factor subfertility.
Cochrane Database Syst Rev. 2013 Aug 23;8:CD005071. doi: 10.1002/14651858.CD005071.pub4. Epub 2013 Aug 23.
Abstract/Text BACKGROUND: Male factors leading to subfertility account for at least half of all cases of subfertility worldwide. Although some causes of male subfertility are treatable, treatment of idiopathic male factor subfertility remains empirical. Researchers have used gonadotrophins to improve sperm parameters in idiopathic male factor subfertility with the ultimate goal of increasing birth and pregnancy rates, but results have been conflicting.
OBJECTIVES: To determine the effect of systemic follicle-stimulating hormone (FSH) on live birth and pregnancy rates when administered to men with idiopathic male factor subfertility .
SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register (14 January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 12 of 12, 2012), Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE (1946 to 14 January 2013), Ovid EMBASE (1980 to week 2 of 2013), Ovid PsycINFO (1806 to week 2 of 2013), trial registers for ongoing and registered trials at ClinicalTrials.gov (19 January 2013), the World Health Organisation International Trials Registry Platform (19 January 2013), The Cochrane Library Database of Abstracts of Reviews of Effects (19 January 2013) and OpenGrey for grey literature from Europe (19 January 2013). Searches were not limited by language. Bibliographies of included and excluded trials and abstracts of major meetings were searched for additional trials.
SELECTION CRITERIA: Randomised controlled trials (RCTs) in which gonadotrophins were compared with placebo or no treatment for participants with idiopathic male factor subfertility.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials, assessed risk of bias and extracted data on live birth, pregnancy and adverse effects. We included data on pregnancies that occurred during or after gonadotrophin therapy. Study authors and pharmaceutical companies were asked to provide missing and unpublished data and/or additional information.
MAIN RESULTS: Six RCTs with 456 participants and variable treatment and follow-up periods were included. From the limited data, the live birth rate per couple randomly assigned (27% vs 0%; Peto odds ratio (OR) 9.31, 95% confidence interval (CI) 1.17 to 73.75, one study, 30 participants, very low-quality evidence) and the spontaneous pregnancy rate per couple randomly assigned (16% vs 7%; Peto OR 4.94, 95% CI 2.13 to 11.44, five studies, 412 participants, I(2) = 0%, moderate-quality evidence) were significantly higher in men receiving gonadotrophin treatment than in men receiving placebo or no treatment. No significant difference between groups was noted when intracytoplasmic sperm injection (ICSI) or intrauterine insemination (IUI) was performed. None of the included studies reported miscarriage rates, and adverse events data were sparse.
AUTHORS' CONCLUSIONS: Encouraging preliminary data suggest a beneficial effect on live birth and pregnancy of gonadotrophin treatment for men with idiopathic male factor subfertility, but because the numbers of trials and participants are small, evidence is insufficient to allow final conclusions. Large multi-centre trials with adequate numbers of participants are needed.

PMID 23970458
Rajeev Kumar, Gagan Gautam, Narmada P Gupta
Drug therapy for idiopathic male infertility: rationale versus evidence.
J Urol. 2006 Oct;176(4 Pt 1):1307-12. doi: 10.1016/j.juro.2006.06.006.
Abstract/Text PURPOSE: About half of all infertile men who seek treatment have no specific cause that can be determined for the seminal abnormality. These men are often subject to a number of medical therapies with doubtful efficacy. We reviewed the rationale on which these therapies are advised and determined whether sufficient medical evidence exists to justify their use.
MATERIALS AND METHODS: A literature search was performed using MEDLINE/PubMed, focusing on publications of the last 20 years of drug therapies for idiopathic male factor infertility. Therapies for specific abnormalities such as hypogonadism were excluded. Basic science, in vitro and animal studies suggesting the mechanism of action for male infertility were evaluated as the rationale part of the review, while controlled and uncontrolled human clinical trials were reviewed as evidence for drug use.
RESULTS: There is no evidence in support of androgens and gonadotropins for enhancing male fertility. These agents may instead act as contraceptives with significant side effects. There is insufficient evidence regarding the role of antiestrogens, aromatase inhibitors and antioxidants. No drug therapy has proved to be clearly beneficial for idiopathic oligoasthenoteratospermia.
CONCLUSIONS: Drug therapy for idiopathic male infertility is at best empirical. There is no clear benefit of using any medication in these patients. Moreover, androgens should not be used because they may actually suppress spermatogenesis.

PMID 16952617
Abstract/Text Spermatozoa recovered from testicular biopsies can be used through intracytoplasmic sperm injection (ICSI) to achieve a pregnancy. To assess the likelihood of successful testicular sperm extraction (TESE) in men suffering from severe oligo- or azoospermia, bilateral biopsy specimens were obtained. Following semi-thin sectioning, the morphology of testicular samples was graded according to a modified Johnsen score. TESE was performed in parallel to this histological examination. The number of isolated spermatozoa was assessed in a semiquantitative way. From 103 patients investigated, 64 (62.1%) showed azoospermia in a preceding semen analysis and 29 (28.2%) patients had sperm concentrations between 0.1 and 1 x 10(6)/ml. In 10 patients who had higher sperm counts, most spermatozoa were non-motile. Spermatozoa could be detected after TESE in the testicular tissue of 49 (77%) azoospermic men. When follicle stimulating hormone (FSH) concentration was normal, most patients had detectable spermatozoa after TESE. Nearly one-third of patients with mildly elevated FSH had no spermatozoa. Thirty-nine percent of patients in whom FSH was elevated to more than twice normal and 50% of patients with grossly elevated FSH had no detectable spermatozoa. In all, 82.8% of men with sperm concentrations between 0.1 and 1x10(6)/ml in their ejaculate showed spermatozoa in the tissue sample after TESE. Our data demonstrate that, contrary to previous recommendations, infertile men with azoospermia and high FSH values should be reconsidered for testicular biopsy, provided that tissue samples can be cryopreserved for later TESE/ICSI treatment.

PMID 9647552
P N Schlegel, P S Li
Microdissection TESE: sperm retrieval in non-obstructive azoospermia.
Hum Reprod Update. 1998 Jul-Aug;4(4):439.
Abstract/Text
PMID 9825858
Hiroshi Okada, Masaki Dobashi, Takafumi Yamazaki, Isao Hara, Masato Fujisawa, Soichi Arakawa, Sadao Kamidono
Conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia.
J Urol. 2002 Sep;168(3):1063-7. doi: 10.1097/01.ju.0000025397.03586.c4.
Abstract/Text PURPOSE: We established a practical and safe strategy for testicular sperm extraction (TESE) in patients with nonobstructive azoospermia and compared conventional with microdissection TESE.
MATERIALS AND METHODS: In a retrospective comparative study 46 patients, including 22 with obstructive and 24 with nonobstructive azoospermia, underwent conventional TESE. Another 100 patients, including 26 with obstructive and 74 with nonobstructive azoospermia, underwent microdissection TESE. Conventional TESE was performed via 3 small 5 mm. incisions in the tunica albuginea. Microdissection TESE was performed by making a 3 to 4 cm. incision in the tunica albuginea under operating microscopy, avoiding the underlying testicular artery. Seminiferous tubules that appeared dilated and opaque were harvested. Sperm recovery rates were compared, as were complication rates assessed by ultrasonographic and endocrinological evaluations.
RESULTS: In obstructive azoospermia cases the sperm recovery rate was 100% for each procedure. In nonobstructive azoospermia cases sperm were recovered in 16.7% and 44.6% by conventional and microdissection TESE, respectively (p = 0.0271). In cases of histologically diagnosed maturation arrest the sperm recovery rate was 37.5% and 75%, respectively (p = 0.22585). In cases of the Sertoli-cell-only syndrome the sperm recovery rate was 6.3% and 33.9%, respectively (p = 0.0494). We identified dilated and opaque seminiferous tubules containing spermatozoa under operating microscopy in 22.2% of patients with maturation arrest and in 63.2% with the Sertoli-cell-only syndrome. The complication rate was significantly lower for microdissection than for conventional TESE.
CONCLUSIONS: In nonobstructive cases, especially those of the Sertoli-cell-only syndrome, microdissection TESE can effectively retrieve spermatozoa and minimize the risk of complications.

PMID 12187223

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