今日の臨床サポート

挙児希望(不妊)

著者: 佐藤幸保 高松赤十字病院 産婦人科

監修: 杉野法広 山口大学 産科婦人科学

著者校正/監修レビュー済:2021/04/14
参考ガイドライン:
  1. 日本産科婦人科学会/日本産婦人科医会:産婦人科診療ガイドライン 婦人科外来編2020
患者向け説明資料

概要・推奨   

  1. 不妊原因検索の1次検査(一般不妊スクリーニング検査)として、基礎体温測定、経腟超音波検査、血中ホルモン検査、クラミジア抗体検査(IgA、IgG)、卵管疎通性検査(子宮卵管造影など)、精液検査、精子-頸管粘液適合試験(フーナーテスト)を行う(推奨度1)。
  1. 血中ホルモン検査としては、卵胞期初期(月経周期3~7日目)に血中LH、FSH、E2、プロラクチン、テストステロン、TSHを測定し、黄体期中期(排卵後7日目前後)に血中プロゲステロンを測定する(推奨度1)。
  1. 37歳以上あるいは不妊期間3年以上の女性では、体外受精の選択肢を早期に提示する(推奨度2)。
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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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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:
佐藤幸保 : 特に申告事項無し[2021年]
監修:杉野法広 : 研究費・助成金など(浜田市,あすか製薬)[2021年]

改訂のポイント:
  1. 産婦人科診療ガイドライン 婦人科外来編2020の主要項目を追加した。

病態・疫学・診察

疾患(疫学・病態)  
  1. 不妊症とは「妊娠活動を1年以上行っても妊娠に至らない病態」をいう[1]
  1. 原発性不妊症(妊娠歴なし)と続発性不妊症(妊娠歴あり)に分類される。
  1. WHOの調査では、女性側に原因41%、男性側に原因24%、男女ともに原因24%、原因不明11%とされている。
  1. わが国において妊娠を望んでいるカップルの約10~15%が不妊で、その約30%は原因不明とされている。
  1. 妊娠成立には「排卵」「受精」「卵割」「着床」の4つのステップが必要である。それにしたがって、本稿では女性不妊症の原因を①排卵障害、②受精障害、③卵割障害、④着床障害の4つに分類する。
①排卵障害(排卵がうまく起こらない、ときどきしか起こらない)
②受精障害(卵子と精子とが出会えない、出会ってもうまく受精しない)
③卵割障害(受精卵の分割がうまくいかず胚盤胞まで到達しない)
④着床障害(胚盤胞が子宮内膜に着床できない)
  1. 男性不妊症の原因には、①造精機能障害(非閉塞性乏精子症/無精子症)82.6%、②性機能障害(勃起障害、射精障害)13.5%、③精路通過障害(閉塞性乏精子症/無精子症)3.9%がある。
  1. 非閉塞性無精子症の多くを占める高ゴナドトロピン(FSH)性精巣機能低下症では根本的治療は困難であり、顕微鏡下精巣内精子採取術(MD-TESE)で得られた少数精子を用いた体外受精(顕微授精)が必要となることが多い。
  1. 低ゴナドトロピン(FSH)性精巣機能低下症の原因の一つである精索静脈瘤では、手術によりその40~70%に精液所見の改善がみられる。
  1. 閉塞性乏精子症/無精子症では、精路再建術を行うことで精液所見の改善が期待できる。
 
妊娠成立に必要な4つのステップと女性不妊症の原因

出典

img1:  著者提供
 
 
問診・診察のポイント  
  1. 月経の異常[1]
  1. 月経周期の異常(正常周期とは25~38日かつ最長-最短周期<7日)は排卵障害の存在を示唆する。

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文献 

著者: Remah M Kamel
雑誌名: Reprod Biol Endocrinol. 2010 Mar 6;8:21. doi: 10.1186/1477-7827-8-21. Epub 2010 Mar 6.
Abstract/Text BACKGROUND: Infertility is defined as inability of a couple to conceive naturally after one year of regular unprotected sexual intercourse. It remains a major clinical and social problem, affecting perhaps one couple in six. Evaluation usually starts after 12 months; however it may be indicated earlier. The most common causes of infertility are: male factor such as sperm abnormalities, female factor such as ovulation dysfunction and tubal pathology, combined male and female factors and unexplained infertility.
OBJECTIVES: The aim of this study is to provide the healthcare professionals an evidence-based management protocol for infertile couples away from medical information overload.
METHODS: A comprehensive review where the literature was searched for "Management of infertility and/or infertile couples" at library website of University of Bristol (MetaLib) by using a cross-search of different medical databases besides the relevant printed medical journals and periodicals. Guidelines and recommendations were retrieved from the best evidence reviews such as that from the American College of Obstetricians and Gynaecologists (ACOG), American Society for Reproductive Medicine (ASRM), Canadian Fertility and Andrology Society (CFAS), and Royal College of Obstetricians and Gynaecologists (RCOG).
RESULTS: A simple guide for the clinicians to manage the infertile couples.
CONCLUSIONS: The study deploys a new strategy to translate the research findings and evidence-base recommendations into a simplified focused guide to be applied on routine daily practice. It is an approach to disseminate the recommended medical care for infertile couple to the practicing clinicians.

PMID 20205744  Reprod Biol Endocrinol. 2010 Mar 6;8:21. doi: 10.1186/1・・・
著者: S Palomba, A Falbo, F Giallauria, T Russo, M Rocca, A Tolino, F Zullo, F Orio
雑誌名: Hum Reprod. 2010 Nov;25(11):2783-91. doi: 10.1093/humrep/deq254. Epub 2010 Sep 21.
Abstract/Text BACKGROUND: Clomiphene citrate (CC) is the first-line therapy for the induction of ovulation in infertile women with polycystic ovary syndrome (PCOS), but ∼20% of patients are unresponsive. The aim of the current study was to test the hypothesis that a 6-week intervention that consisted of structured exercise training (SET) and hypocaloric diet increases the probability of ovulation after CC in overweight and obese CC-resistant PCOS patients.
METHODS: A cohort of 96 overweight and obese CC-resistant PCOS patients was enrolled consecutively in a three-arm randomized, parallel, controlled, assessor-blinded clinical trial. The three interventions were: SET plus hypocaloric diet for 6 weeks (Group A); 2 weeks of observation followed by one cycle of CC therapy (Group B); and SET plus hypocaloric diet for 6 weeks, with one cycle of CC after the first 2 weeks (Group C). The primary end-point was the ovulation rate. Other reproductive data, as well as anthropometric, hormonal and metabolic data, were also collected and considered as secondary end points.
RESULTS: After 6 weeks of SET plus hypocaloric diet, the ovulation rate was significantly (P =0.008) higher in Group C [12/32 (37.5%)] than in Groups A [4/32 (12.5%)] and B [3/32 (9.4%)] with relative risks of 3.9 [95% confidence interval (CI) 1.1-8.3; P = 0.035] and 4.0 (95% CI 1.2-12.8; P = 0.020) compared with Groups A and B, respectively. Compared with baseline, in Groups A and C, a significant improvement in clinical and biochemical androgen and insulin sensitivity indexes was observed. In the same two groups, the insulin sensitivity index was significantly (P < 0.05) better than that in Group B.
CONCLUSIONS: In overweight and obese CC-resistant PCOS patients, a 6-week intervention of SET and a hypocaloric diet was effective in increasing the probability of ovulation under CC treatment. The study was registered at Clinical trials.gov:NCT0100468.

PMID 20858697  Hum Reprod. 2010 Nov;25(11):2783-91. doi: 10.1093/humre・・・
著者: Thomas I Siebert, Thinus F Kruger, Daniel W Steyn, Saleema Nosarka
雑誌名: Fertil Steril. 2006 Nov;86(5):1432-7. doi: 10.1016/j.fertnstert.2006.06.014. Epub 2006 Sep 27.
Abstract/Text OBJECTIVE: The aim of this literature search is to establish if metformin is efficacious when given to clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) patients.
DESIGN: Medline database was searched from 1 January 1980 to 1 January 2005. Inclusion criteria were prospective randomized control trials where metformin was randomized either with placebo or CC to induce ovulation in the CC-resistant patient.
RESULT(S): Group 1: Four trials were prospective double-blind placebo controlled. When the data of the four trials were pooled, the overall effect of the addition of metformin in the CC patient was P=.0006 with a 95% confidence interval (CI) of odds ratio (OR) 1.81-8.84. Group 2: In two trials the randomization was only prospective. When the data of these two trials were pooled, the overall effect of the addition of metformin in the CC-resistant patient was P<.0001 with a 95% CI of OR 6.24-70.27. Groups 1 and 2: The combined data show an overall effect of P<.0001 with a 95% CI of OR 3.59-12.96.
CONCLUSION(S): The addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction.

PMID 17007847  Fertil Steril. 2006 Nov;86(5):1432-7. doi: 10.1016/j.fe・・・
著者: Sebastian Franik, Stephanie M Eltrop, Jan Am Kremer, Ludwig Kiesel, Cindy Farquhar
雑誌名: Cochrane Database Syst Rev. 2018 May 24;5:CD010287. doi: 10.1002/14651858.CD010287.pub3. Epub 2018 May 24.
Abstract/Text BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC).
OBJECTIVES: To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI).
SEARCH METHODS: We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status.
SELECTION CRITERIA: We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods.
MAIN RESULTS: This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary.
AUTHORS' CONCLUSIONS: Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.

PMID 29797697  Cochrane Database Syst Rev. 2018 May 24;5:CD010287. doi・・・
著者: Hatem Abu Hashim
雑誌名: Arch Gynecol Obstet. 2012 Jun;285(6):1737-45. doi: 10.1007/s00404-012-2261-2. Epub 2012 Mar 6.
Abstract/Text Polycystic ovary syndrome (PCOS) is a prevalent and heterogeneous condition affecting 4-8% of reproductive age women. It is the most common cause of chronic anovulation and is associated with hyperandrogenemia. Clomiphene citrate (CC) is considered as the first-line therapy for ovulation induction in these patients. Despite progress in understanding the pathophysiology of PCOS over the past 20 years, many questions persist to the extent that PCOS was described as "A Riddle Wrapped in a Mystery inside an Enigma". On the other hand, a recent publication from the Centers for Disease Control suggested that CC may be associated with an increased risk of birth defects. The purpose of this review is to critically evaluate and summarize the current literature regarding CC alternatives for the initial management of PCOS focusing specifically on the roles of weight loss and other approaches to ovulation induction as insulin-sensitizing drugs, aromatase inhibitors, minimal stimulation protocol, gonadotrophins and surgery (laparoscopic ovarian drilling). Finally, the efficacy of intrauterine insemination with CC for the initial management of PCOS will be evaluated.

PMID 22392485  Arch Gynecol Obstet. 2012 Jun;285(6):1737-45. doi: 10.1・・・
著者: R Homburg, M L Hendriks, T E König, R A Anderson, A H Balen, M Brincat, T Child, M Davies, T D'Hooghe, A Martinez, M Rajkhowa, R Rueda-Saenz, P Hompes, C B Lambalk
雑誌名: Hum Reprod. 2012 Feb;27(2):468-73. doi: 10.1093/humrep/der401. Epub 2011 Nov 28.
Abstract/Text BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment.
METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR.
RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI.
CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

PMID 22128296  Hum Reprod. 2012 Feb;27(2):468-73. doi: 10.1093/humrep/・・・
著者: Cindy Farquhar, Julie Brown, Jane Marjoribanks
雑誌名: Cochrane Database Syst Rev. 2012 Jun 13;6:CD001122. doi: 10.1002/14651858.CD001122.pub4. Epub 2012 Jun 13.
Abstract/Text BACKGROUND: Surgical ovarian wedge resection was the first established treatment for women with anovulatory polycystic ovary syndrome (PCOS) but was largely abandoned both due to the risk of postsurgical adhesions and the introduction of medical ovulation induction. However, women with PCOS who are treated with medical ovulation induction, with drugs such as gonadotrophins, often have an over-production of follicles which may result in ovarian hyperstimulation syndrome and multiple pregnancies. Moreover, gonadotrophins, though effective, are costly and time-consuming and their use requires intensive monitoring. Surgical therapy with laparoscopic ovarian 'drilling' (LOD) may avoid or reduce the need for medical ovulation induction, or may facilitate its usefulness. The procedure can be done on an outpatient basis with less trauma and fewer postoperative adhesions than with traditional surgical approaches. Many uncontrolled observational studies have claimed that ovarian drilling is followed, at least temporarily, by a high rate of spontaneous ovulation and conception, or that subsequent medical ovulation induction becomes easier.
OBJECTIVES: To determine the effectiveness and safety of laparoscopic ovarian drilling compared with ovulation induction for subfertile women with clomiphene-resistant PCOS.
SEARCH METHODS: We used the search strategy of the Menstrual Disorders and Subfertility Group (MDSG) to search the MDSG Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO. The keywords included polycystic ovary syndrome, laparoscopic ovarian drilling, electrocautery and diathermy. Searches were conducted in September 2011, and a further search of the MDSG Trials Register was made on 14 May 2012.
SELECTION CRITERIA: We included randomised controlled trials of subfertile women with clomiphene-resistant PCOS who undertook laparoscopic ovarian drilling in order to induce ovulation.
DATA COLLECTION AND ANALYSIS: This is an update of a previously updated review. There were nine RCTs in the previous version; an additional 16 trials were added in the current (2012) update. All trials were assessed for quality. The primary outcomes were live birth and multiple pregnancy. The secondary outcomes were rate of miscarriage, ovulation and pregnancy rates, ovarian hyperstimulation syndrome (OHSS), quality of life and cost.
MAIN RESULTS: Nine trials, including 1210 women, reported on the primary outcome of live birth rate per couple. Live births were reported in 34% of women in the LOD groups and 38% in other medical treatment groups. There were five different comparisons with LOD and there was no evidence of a difference in live births when compared with clomiphene citrate + tamoxifen (OR 0.81; 95% CI 0.42 to 1.53; P = 0.51, 1 trial, n = 150), gonadotrophins (OR 0.97; 95% CI 0.59 to 1.59; P = 0.89, I(2) = 0%, 2 trials, n = 318), aromatase inhibitors (OR 0.84; 95% CI 0.54 to 1.31; P = 0.44, I(2) = 0%, 2 trials, n = 407) or clomiphene citrate (OR 1.21; 95%CI 0.64 to 2.32; 1 trial, n=176, P= 0.05). There was evidence of significantly fewer live births following LOD compared with clomiphene citrate + metformin (OR 0.44; 95% CI 0.24 to 0.82; P = 0.01, I(2) = 78%, 2 trials, n = 159); the high heterogeneity in this subgroup could not be explained by population differences or differences in quality of the trials.Thirteen trials reported on multiple pregnancies (n= 1305 women). There were no cases of multiple pregnancies in either group for clomiphene citrate or aromatase inhibitors compared with LOD. The rate of multiple pregnancies was significantly lower in the LOD group compared with trials using gonadotrophins (OR 0.13; 95% CI 0.03 to 0.52; P=0.004, I(2) = 0%, 5 trials, n = 166).
AUTHORS' CONCLUSIONS: There was no evidence of a significant difference in rates of clinical pregnancy, live birth or miscarriage in women with clomiphene-resistant PCOS undergoing LOD compared to other medical treatments. The reduction in multiple pregnancy rates in women undergoing LOD makes this option attractive. However, there are ongoing concerns about the long-term effects of LOD on ovarian function.

PMID 22696324  Cochrane Database Syst Rev. 2012 Jun 13;6:CD001122. doi・・・
著者: Francesca Cristello, Vito Cela, Paolo Giovanni Artini, Andrea Riccardo Genazzani
雑誌名: Gynecol Endocrinol. 2005 Dec;21(6):340-52. doi: 10.1080/09513590500463360.
Abstract/Text Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hirsutism, obesity, hyperandrogenism and insulin resistance. The syndrome is often accompanied by infertility because of anovulation. Many approaches have been proposed to solve this problem, with the most commonly used therapies being ovarian drilling and pharmacological ovulation induction. Ovarian drilling is a procedure in which a laser fiber or electro-surgical needle punctures the ovary four to ten times. Side-effects are rare and often related to surgery itself. Pharmacological strategies include administration of metformin and insulin-sensitizing agents, clomiphene citrate (CC), gonadotropins and aromatase inhibitors. Metformin appears valuable in increasing ovulation rate, menstrual cyclicity and pregnancy rate. CC is an oral estrogen antagonist that raises circulating concentrations of follicle-stimulating hormone (FSH) and induces follicular growth in most women with PCOS and anovulation. Failure to respond is associated with high body mass index and high androgen levels. Aromatase inhibitors mimic the central reduction of negative feedback through which CC works. Ovulation induction with recombinant FSH has proved successful, but treatment requires skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome. The hypothetical deleterious effects of the high luteinizing hormone concentrations observed in PCOS patients seem to be related to the concomitant hyperinsulinemia (and/or insulin resistance). A thorough understanding of the syndrome and a careful assessment of each patient are the mainstays for choosing an appropriate treatment regimen.

PMID 16390783  Gynecol Endocrinol. 2005 Dec;21(6):340-52. doi: 10.1080・・・
著者: E Hughes, J Brown, J J Collins, C Farquhar, D M Fedorkow, P Vandekerckhove
雑誌名: Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000155. doi: 10.1002/14651858.CD000155.pub2. Epub 2007 Jul 18.
Abstract/Text BACKGROUND: Endometriosis is the finding of endometrial glands or stroma in sites other than the uterine cavity. Endometriosis appears to be an oestrogen dependent condition. This hormonal dependency has prompted the therapeutic use of ovulation suppression agents, in an effort to improve subsequent fertility.
OBJECTIVES: To assess the effectiveness of ovulation suppression agents, including danazol, progestins and oral contraceptives, in the treatment of endometriosis-associated subfertility in improving pregnancy outcomes including live birth.
SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Sub-fertility Group's specialised register of trials (searched October 5th, 2007) the Cochrane Register of Controlled Trials (The Cochrane Library, Issue 3, 2007), MEDLINE (1966-October 2007), EMBASE (1980 - October 2007) and reference lists of articles.
SELECTION CRITERIA: Randomised trials comparing an ovulation suppression agent with placebo or no treatment, or a suppressive agent with danazol or a GnRH with oral contraception in women with endometriosis. A total of twenty three RCTs comparing an ovulation suppression agent with placebo or no treatment, or a suppressive agent with danazol or a GnRH with oral contraception were identified.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality. We contacted study authors for additional information. Quality was assessed by of method of randomization,allocation concealment, blinding, completeness of follow-up, presence or absence of crossover and co-intervention. 2 x 2 tables were generated for all relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique. Statistical heterogeneity was assessed using the I(2) test of heterogeneity. Subgroup analysis was conducted on those couples clearly identifiable as infertile or wanting to conceive.
MAIN RESULTS: Twenty four trials were included. The odds ratio for pregnancy following ovulation suppression versus placebo or no treatment for all women randomised was 0.79 (95% CI 0.54 to 1.14), P = 0.21 and 0.80 (95% CI 0.51 to 1.24), P = 0.32 respectively for subfertile couples only despite the use of a variety of suppression agents. There was no evidence of benefit from the treatment. The common odds ratio for pregnancy following all agents versus danazol for all women randomised was 1.38 (95% CI 1.05 to 1.82), P = 0.02 and OR 1.37 (95% CI 0.94 to 1.99), P = 0.10 for subfertile couples only. When GnRHa and danazol were directly compared, OR was 1.45 (95% CI 1.08 to 1.95) P = 0.01 for all women randomised and OR 1.63( 95% CI 1.12 to 2.37), P = 0.01 for subfertile couples only in favour of GnRH. No effect was observed for GnRH compared with oral contraception; OR 0.99 (95% CI 0.52 to 1.89), P = 0.98 for all women randomised and OR 0.79 ( 95% CI 0.37 to 1.69), P = 0.55. In all analyses the data were statistically homogeneous (I(2)=0%).
AUTHORS' CONCLUSIONS: There is no evidence of benefit in the use of ovulation suppression in subfertile women with endometriosis who wish to conceive.

PMID 17636607  Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000155. d・・・
著者: Tal Z Jacobson, James Mn Duffy, David Barlow, Cindy Farquhar, Philippe R Koninckx, David Olive
雑誌名: Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001398. doi: 10.1002/14651858.CD001398.pub2. Epub 2010 Jan 20.
Abstract/Text BACKGROUND: Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity. It is variable in both its surgical appearance and clinical manifestation, often with poor correlation between the two. Surgical treatment of endometriosis aims to remove visible areas of endometriosis and restore anatomy by the division of adhesions.
OBJECTIVES: To assess the efficacy of laparoscopic surgery in the treatment of subfertility associated with endometriosis. The review aims to compare outcomes of laparoscopic surgical interventions compared to no treatment or medical treatment with regard to improved fertility.
SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials (June 2009), Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to June 2009), EMBASE (1980 to June 2009), and reference lists of articles.
SELECTION CRITERIA: Trials were selected if they were randomised and compared the effectiveness of laparoscopic surgery in the treatment of subfertility associated with endometriosis versus other treatment modalities or placebo.
DATA COLLECTION AND ANALYSIS: Two studies were eligible for inclusion within the review. Both studies compared laparoscopic surgical treatment of minimal and mild endometriosis compared with diagnostic laparoscopy only. The recorded outcomes included live birth, pregnancy, fetal losses, and complications of surgery.
MAIN RESULTS: When combining live birth rate and ongoing pregnancy after 20 weeks, meta-analysis demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only. The odds ratio (OR) was 1.64 (95% confidence interval (Cl) 1.05 to 2.57) in favour of laparoscopic surgery. Meta-analysis also demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only in terms of clinical pregnancy rates, with an OR of 1.66 (95% Cl 1.09 to 2.51) favouring laparoscopic surgery. The results still need to be interpreted with caution as Marcoux 1997 reported a large positive effect of surgery whereas Gruppo Italiano reported a small negative effect. When considering fetal losses, meta-analysis did not demonstrate an effect of laparoscopic surgery when compared to diagnostic laparoscopy only. The OR was 1.33 (95% Cl 0.60 to 2.94) favouring diagnostic laparoscopy only.
AUTHORS' CONCLUSIONS: The use of laparoscopic surgery in the treatment of subfertility related to minimal and mild endometriosis may improve future fertility.

PMID 20091519  Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001398. d・・・
著者: Laura Benschop, Cindy Farquhar, Nicolien van der Poel, Maas Jan Heineman
雑誌名: Cochrane Database Syst Rev. 2010 Nov 10;(11):CD008571. doi: 10.1002/14651858.CD008571.pub2. Epub 2010 Nov 10.
Abstract/Text BACKGROUND: Endometriomata are cysts of endometriosis in the ovaries. As artificial reproductive technology (ART) cycles involve oocyte pickup from the ovaries, endometriomata may interfere with the outcome of ART.
OBJECTIVES: To determine the effectiveness and safety of surgery, medical treatment, combination therapy or no treatment for improving reproductive outcomes among women with endometriomata, prior to undergoing ART cycles.
SEARCH STRATEGY: The review authors searched: Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials, CENTRAL (The Cochrane Library), EMBASE, MEDLINE, PubMed, PsycINFO, CINAHL, DARE, trial registers for ongoing and registered trials, citation indexes, conference abstracts on the ISI Web of Knowledge, Clinical Study Results, OpenSIGLE (July 2010) and handsearched Fertility and Sterility (2008 to 2010).
SELECTION CRITERIA: Randomised controlled trials of any medical, surgical or combination therapy or expectant management for endometriomata prior to ART.
DATA COLLECTION AND ANALYSIS: The trials were independently identified and assessed for risk of bias by two authors. The authors of the trials that were potentially eligible for inclusion were contacted for additional information. Outcomes were expressed as Peto odds ratios and mean differences (MD).
MAIN RESULTS: Eleven trials were identified of which seven were excluded and four with 312 participants were included.No trial reported live birth outcomes. One trial compared gonadotropin-releasing hormone (GnRH) agonist with GnRH antagonist. There was no evidence of a difference for clinical pregnancy rate (CPR), however the number of mature oocytes retrieved (NMOR) was greater with GnRH agonists (MD -1.60, 95% CI -2.44 to -0.76) and the ovarian response was increased (estradiol (E2) levels on day of human chorionic gonadotropin (hCG) injection) (MD -456.30, 95% CI -896.06 to -16.54).Surgery (aspiration or cystectomy) versus expectant management (EM) showed no evidence of a benefit for clinical pregnancy with either technique. Aspiration was associated with greater NMOR (MD 0.50, 95% CI 0.02 to 0.98) and increased ovarian response (E2 levels on day of hCG injection) (MD 685.3, 95% CI 464.50 to 906.10) compared to EM.Cystectomy was associated with a decreased ovarian response to controlled ovarian hyperstimulation (COH) (MD -510.00, 95% CI -676.62 to -343.38); no evidence of an effect on the NMOR compared to EM. Aspiration versus cystectomy showed no evidence of a difference in CPR or the NMOR.
AUTHORS' CONCLUSIONS: There was no evidence of an effect on reproductive outcomes in any of the four included trials. Further RCTs of management of endometrioma in women undergoing ART are required.

PMID 21069706  Cochrane Database Syst Rev. 2010 Nov 10;(11):CD008571. ・・・
著者: N Carroll, J R Palmer
雑誌名: Fertil Steril. 2001 Apr;75(4):656-60.
Abstract/Text OBJECTIVE: To compare the efficacy of intrauterine insemination (IUI) and intracervical insemination (ICI) when used by fertile single women in a donor insemination program.
DESIGN: Prospective randomized crossover study.
SETTING: Donor insemination program (not an infertility clinic).
PATIENT(S): Single fertile women choosing to inseminate with frozen donor semen.
INTERVENTION(S): Clients received procreative counseling and screening and were then randomly assigned to begin office insemination with ICI or IUI. If additional insemination cycles were required, the clients used the method opposite their previous method of insemination until pregnancy was achieved.
MAIN OUTCOME MEASURE(S): Monthly fecundity rate was compared between the two methods of insemination.
RESULT(S): Sixty-two women contributed a total of 189 cycles, 94 by IUI and 95 by ICI. The monthly fecundity rate for IUI was 15%, as compared with 9% for ICI, (P=0.14). When the analysis was confined to cycles in which only one insemination was performed (64 IUI and 65 ICI cycles), the monthly fecundity rates were 14% for IUI and 5% for ICI (P=0.04).
CONCLUSION(S): Intrauterine insemination with frozen donor sperm is more effective than intracervical insemination for single women without known fertility problems.

PMID 11287014  Fertil Steril. 2001 Apr;75(4):656-60.
著者: Richard P Dickey, Steven N Taylor, Peter Y Lu, Belinda M Sartor, Phillip H Rye, Roman Pyrzak
雑誌名: Fertil Steril. 2002 Nov;78(5):1088-95.
Abstract/Text OBJECTIVE: To determine how diagnosis, age, sperm quality, and number of preovulatory follicles affect pregnancy rates when multiple cycles of clomiphene citrate (CC)-IUI are performed.
DESIGN: Fifteen-year prospective observational study.
SETTING: Private infertility clinic.
PATIENT(S): Three thousand, three hundred eighty-one cycles of husband or donor IUI.
INTERVENTION(S): Ovulation induction with CC and IUI.
MAIN OUTCOME MEASURE(S): Per-cycle pregnancy rate (PR), cumulative pregnancy rate (CPR).
RESULT(S): Pregnancy rates remained constant through four cycles, then fell significantly for diagnoses other than ovulatory dysfunction. Mean PRs for cycles 1-4 were significantly lower for patients with the following characteristics: age >/=43 years, poor semen quality, single preovulatory follicles, and diagnoses other than ovulatory dysfunction. Additional cycles of CC-IUI compensated for low PRs because of age, semen quality, or number of follicles. After four cycles, CPRs were 46% for ovulatory dysfunction; 38% for cervical factor, male factor, and unexplained infertility; 34% for endometriosis; and 26% for tubal factor. After six cycles, CPRs were 65% for ovulation dysfunction, 35% for endometriosis, and unchanged for other diagnoses.
CONCLUSION(S): Clomiphene citrate-intrauterine insemination should be performed for a minimum of four cycles. Additional cycles of CC-IUI can compensate for low pregnancy rates due to age, semen quality, or follicle number in patients with ovulation dysfunction.

PMID 12413999  Fertil Steril. 2002 Nov;78(5):1088-95.
著者: Susanne M Veltman-Verhulst, Edward Hughes, Reuben Olugbenga Ayeleke, Ben J Cohlen
雑誌名: Cochrane Database Syst Rev. 2016 Feb 19;2:CD001838. doi: 10.1002/14651858.CD001838.pub5. Epub 2016 Feb 19.
Abstract/Text BACKGROUND: Intra-uterine insemination (IUI) is a widely used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive thAppendixan in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rate. This is an update of a Cochrane review (Veltman-Verhulst 2012) originally published in 2006 and updated in 2012.
OBJECTIVES: To determine whether, for couples with unexplained subfertility, IUI improves the live birth rate compared with timed intercourse (TI), or expectant management, both with and without ovarian hyperstimulation (OH).
SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (formerly Cochrane Menstrual Disorders and Subfertility Group) Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, inception to Issue 11, 2015), Ovid MEDLINE, Ovid EMBASE, PsycINFO and trial registers, all from inception to December 2015 and reference lists of articles. Authors of identified studies were contacted for missing or unpublished data. The evidence is current to December 2015.
SELECTION CRITERIA: Truly randomised controlled trial (RCT) comparisons of IUI versus TI, in natural or stimulated cycles. Only couples with unexplained subfertility were included.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, quality assessment and data extraction. We extracted outcomes, and pooled data and, where possible, we carried out subgroup and sensitivity analyses.
MAIN RESULTS: We included 14 trials including 1867 women. IUI versus TI or expectant management both in natural cycleLive birth rate (all cycles)There was no evidence of a difference in cumulative live births between the two groups (Odds Ratio (OR) 1.60, 95% confidence interval (CI) 0.92 to 2.78; 1 RCT; n = 334; moderate quality evidence). The evidence suggested that if the chance of a live birth in TI was assumed to be 16%, that of IUI would be between 15% and 34%.Multiple pregnancy rateThere was no evidence of a difference in multiple pregnancy rate between the two treatment groups (OR 0.50, 95% CI 0.04 to 5.53; 1 RCT; n = 334; moderate quality evidence). IUI versus TI or expectant management both in stimulated cycleLive birth rate (all cycles)There was no evidence of a difference between the two treatment groups (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs; n = 208; I(2) = 72%; moderate quality evidence). The evidence suggested that if the chance of achieving a live birth in TI was assumed to be 26%, the chance of a live birth with IUI would be between 23% and 50%.Multiple pregnancy rateThere was no evidence of a difference in multiple pregnancy rates between the two treatment groups (OR 1.46, 95% CI 0.55 to 3.87; 4 RCTs, n = 316; I(2) = 0%; low quality evidence). IUI in a natural cycle versus IUI in a stimulated cycle Live birth rate (all cycles)An increase in live birth rate was found for women who were treated with IUI in a stimulated cycle compared with those who underwent IUI in natural cycle (OR 0.48, 95% CI 0.29 to 0.82; 4 RCTs, n = 396; I(2) = 0%; moderate quality evidence). The evidence suggested that if the chance of a live birth in IUI in a stimulated cycle was assumed to be 25%, the chance of a live birth in IUI in a natural cycle would be between 9% and 21%.Multiple pregnancy rateThere was no evidence of a difference in multiple pregnancy rate between the two treatment groups (OR 0.33, 95% CI 0.01 to 8.70; 2 RCTs; n = 65; low quality evidence). IUI in a stimulated cycle versus TI or expectant management in a natural cycleLive birth rate (all cycles)There was no evidence of a difference in live birth rate between the two treatment groups (OR 0.82, 95% CI 0.45 to 1.49; 1 RCT; n = 253; moderate quality evidence). The evidence suggested that if the chance of a live birth in TI or expectant management in a natural cycle was assumed to be 24%, the chance of a live birth in IUI in a stimulated cycle would be between 12% and 32%.Multiple pregnancy rateThere was no evidence of a difference in multiple pregnancy rate between the two treatment groups (OR 2.00, 95% CI 0.18 to 22.34; 2 RCTs; n = 304; moderate quality evidence). IUI in natural cycle versus TI or expectant management in stimulated cycle Live birth rate (all cycles)There was evidence of an increase in live births for IUI (OR 1.95, 95% CI 1.10 to 3.44; 1 RCT, n = 342; moderate quality evidence). The evidence suggested that if the chance of a live birth in TI in a stimulated cycle was assumed to be 13%, the chance of a live birth in IUI in a natural cycle would be between 14% and 34%.Multiple pregnancy rateThere was no evidence of a difference in multiple pregnancy rate between the groups (OR 1.05, 95% CI 0.07 to 16.90; 1 RCT; n = 342; moderate quality evidence).The quality of the evidence was assessed using GRADE methods. Quality ranged from low to moderate, the main limitation being imprecision in the findings for both live birth and multiple pregnancy..
AUTHORS' CONCLUSIONS: This systematic review did not find conclusive evidence of a difference in live birth or multiple pregnancy in most of the comparisons for couples with unexplained subfertility treated with intra-uterine insemination (IUI) when compared with timed intercourse (TI), both with and without ovarian hyperstimulation (OH). There were insufficient studies to allow for pooling of data on the important outcome measures for each of the comparisons.

PMID 26892070  Cochrane Database Syst Rev. 2016 Feb 19;2:CD001838. doi・・・

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