今日の臨床サポート 今日の臨床サポート

著者: 堀江昭史 公益財団法人田附興風会 医学研究所北野病院 産婦人科

監修: 岩瀬明 群馬大学大学院医学系研究科産科婦人科学講座

著者校正/監修レビュー済:2024/07/24
参考ガイドライン:
  1. 日本産科婦人科学会:産婦人科診療ガイドライン婦人科外来編2023
  1. 日本生殖医学会:生殖医療の必修知識 2023
患者向け説明資料

改訂のポイント:
  1. 『産婦人科診療ガイドライン2023』の発刊に伴いレビューを行った。
  1. LODを考慮する際の注意点を追記した(Bordewijk EM,et al. Cochrane Database Syst Rev. 2020 Feb 11;2(2):CD001122.)。

概要・推奨   

  1. 無排卵を発症する原理を理解する。
  1. 無排卵の原因疾患を把握する。
  1. 無排卵の治療について理解する。

病態・疫学・診察 

疾患(疫学・病態)  
ポイント:
  1. 無排卵は下記のいずれかの部位の障害によるもので、視床下部・下垂体性と卵巣性の無排卵に大別される[1]
  1. 視床下部から分泌されるGnRHの刺激により、下垂体からFSHとLHが分泌される。FSH、LHの作用により卵巣内の卵胞発育が促進し、卵胞からはエストロゲン(E2)が産生される。E2の産生がピークに達するとLHサージが誘発(ポジティブフィードバック)され、排卵が誘起される。
  1. 性成熟女性において排卵は1カ月に一度起こるが、数カ月に1回の排卵になることを稀発排卵といい、全く排卵が起こらない状態を無排卵症という。
 
視床下部・下垂体性無排卵症:
  1. 視床下部−下垂体−卵巣系の未熟性による排卵障害であることが多く、若年者に多いことが特徴である。
  1. 低ゴナドトロピン性性腺機能低下:FSH、LH値が低くE2値も低い(下垂体腫瘍などによる障害や、多くは神経性やせ症、スポーツ選手に代表的な視床下部の抑制)[1]。なお、軽度の視床下部の障害であれば、FSH、LHは正常値を示す。
  1. 高プロラクチン血症に伴う視床下部GnRH分泌の障害による。
 
卵巣性無排卵症:
  1. Turner症候群など染色体変化により卵子を認めないことが原因:E2は基準値以下で、FSH、LHは高値を示す。
  1. 手術、化学療法、放射線治療による卵巣に障害が加わったことが原因:E2は基準値以下で、FSH、LHは高値を示す。
  1. 黄体化非破裂卵胞(LUF):卵胞は成長し排卵の時期となっても、卵胞が破裂せず、排卵が起こらないまま卵胞が黄体化する病態である。一般的に基礎体温は2相性となり、一見、排卵が生じているように思われるので注意する。
 
多嚢胞性卵巣症候群(polycystic ovary syndrome: PCOS):
  1. LH高値、FSH正常で、続発性無月経の女性の約30%に認める。
問診・診察のポイント  
  1. 妊娠の可能性を否定する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
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文献 

ESHRE Capri Workshop Group.
Health and fertility in World Health Organization group 2 anovulatory women.
Hum Reprod Update. 2012 Sep-Oct;18(5):586-99. doi: 10.1093/humupd/dms019. Epub 2012 May 19.
Abstract/Text BACKGROUND: Disruption of ovulation occurs in different types of clinical infertility. The World Health Organization (WHO) has provided a classification of ovulation disorders. This review focuses on WHO group 2 anovulation.
METHODS: Searches were performed in Medline/PubMed and EMBASE. Each subject summary was presented to the European Society of Human Reproduction and Embryology (ESHRE) Workshop Group, where omissions or disagreements were resolved by discussion.
RESULTS: Disorders resulting in ovulatory disturbances are a relatively common cause of infertility. They occur most frequently in the context of WHO group 2 anovulation as reflected, for example, in the polycystic ovary syndrome (PCOS). The aetiology of PCOS remains unclear but evidence exists for a multifactorial origin with a genetic predisposition. Women with PCOS show an increased time to pregnancy but their eventual family size is not necessarily reduced. Also their frequency of miscarriage does not appear increased. Clomiphene citrate is still the first-line treatment in subfertile anovulatory patients with PCOS, with gonadotrophins and laparoscopic ovarian surgery as second-line options. Aromatase inhibitors show promising results.
CONCLUSIONS: Long-term health risks in patients with WHO group 2 anovulation demand their general health be monitored, even after their reproductive needs have been fulfilled. Metabolic and cardiovascular risk prevention in women with PCOS should start as early as possible. It is not easy to analyse the possible role of PCOS, independent of obesity, metabolic syndrome, insulin resistance and diabetes, on long-term health.

PMID 22611175
Abu Hashim H, Al-Inany H, De Vos M, Tournaye H.
Three decades after Gjönnaess's laparoscopic ovarian drilling for treatment of PCOS; what do we know? An evidence-based approach.
Arch Gynecol Obstet. 2013 Aug;288(2):409-22. doi: 10.1007/s00404-013-2808-x. Epub 2013 Mar 30.
Abstract/Text BACKGROUND: The introduction of laparoscopic ovarian drilling (LOD) by Gjönnaess in 1984 as a substitute for ovarian wedge resection created opportunities for extensive research given its worldwide application for ovulation induction in women with polycystic ovary syndrome (PCOS).
PURPOSE: To critically evaluate and summarize the current body of literature regarding the role of LOD for the management of PCOS entailing its different preoperative, operative and postoperative aspects. In addition, long-term efficacy, cost-effectiveness, patient preference and health-related quality of life issues will be evaluated together with other available alternatives of ovulation induction treatments.
METHODS: A PubMed search was conducted looking for the different trials, reviews and various guidelines relating to the role of LOD in the management of PCOS.
RESULTS: LOD whether unilateral or bilateral is a beneficial second-line treatment in infertile women with clomiphene citrate (CC)-resistant PCOS. It is as effective as gonadotrophin treatment but without the risk of multiple pregnancy or ovarian hyperstimulation and does not require intensive monitoring. Increased responsiveness of the ovary to CC especially in patients who remain anovulatory following LOD is another advantage. Recent evidence suggests that relatively novel oral methods of ovulation induction, e.g. CC plus metformin, CC plus tamoxifen, rosiglitazone plus CC and aromatase inhibitors represent a successful alternative to LOD in CC-resistant PCOS. Meanwhile current evidence does not support LOD as a first-line approach in PCOS-related anovulation or before IVF.
CONCLUSION: LOD is currently recommended as a successful and economical second-line treatment for ovulation induction in women with CC-resistant PCOS.

PMID 23543241
Bordewijk EM, Ng KYB, Rakic L, Mol BWJ, Brown J, Crawford TJ, van Wely M.
Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome.
Cochrane Database Syst Rev. 2020 Feb 11;2(2):CD001122. doi: 10.1002/14651858.CD001122.pub5. Epub 2020 Feb 11.
Abstract/Text BACKGROUND: Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions.
OBJECTIVES: To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance.
SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes.
MAIN RESULTS: This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I2 = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I2 = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I2 = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I2 = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I2 = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I2 = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I2 = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I2 = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose.
AUTHORS' CONCLUSIONS: Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
PMID 32048270
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、渡邉裕次、井ノ口岳洋、梅田将光および日本医科大学多摩永山病院 副薬剤部長 林太祐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:
堀江昭史 : 特に申告事項無し[2024年]
監修:岩瀬明 : 講演料(フェリング・ファーマ(株))[2024年]

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