今日の臨床サポート

早発卵巣不全

著者: 梶原 健 埼玉医科大学病院 産婦人科

監修: 小林裕明 鹿児島大学大学院医歯学総合研究科生殖病態生理学

著者校正/監修レビュー済:2020/11/06
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. 早発卵巣(機能)不全(POIと診断された場合には、内分泌学的検索や遺伝子的検索により原因を検索することが推奨される(推奨度2)
  1. 挙児希望がない場合はホルモン補充療法(HRT)を行う(推奨度2
  1. 挙児希望がある場合は早期に専門とする医師に紹介する(推奨度2
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
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:
梶原 健 : 特に申告事項無し[2021年]
監修:小林裕明 : 講演料(中外製薬株式会社,アストラゼネカ株式会社),奨学(奨励)寄付など(中外製薬株式会社)[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に基づき、主に診断と拳児希望がある場合の治療にについて改訂した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 早発閉経(premature menopause)は卵巣機能が不可逆的に消失した場合の診断名であり、早発卵巣(機能)不全(Primary ovarian insufficiency、POI)はこれらの病態を包含した診断名と位置づけられる。
  1. 排卵障害の病態としてWHOのgroup3に該当する。
  1. POIは40歳未満の続発性無月経で、少なくとも1カ月以上間隔をおいて2回測定し血中FSH値が25mIU/mL以上で低エストロゲン値の場合に診断される。
  1. POIの頻度は40歳未満で約1%、30歳未満0.1%、20歳未満0.01%といわれている[1]。日本人女性では0.1%と報告されている[2]
  1. 原因はX染色体異常、遺伝性、自己免疫性疾患、医原性(手術、化学療法、放射線療法)など種々あるが、大部分は原因不明である。
  1. 治療の主体は、慢性的なエストロゲン欠乏による症状の改善と骨粗鬆症の予防のためのホルモン補充療法である。
  1. 挙児希望がある場合には、排卵誘発を行うが、一般に排卵を回復させ妊娠に至ることはきわめて困難であり、エビデンスの高い有効な治療はない。
  1. ただし、偶発例も含め5~10%妊娠が可能であるといわれている[3]
  1. 症例ごとの評価と治療計画の立案、さらには精神面でのサポートが重要である。
問診・診察のポイント  
問診:
  1. 卵巣手術の既往、放射線療法、抗がん薬などの治療の既往を確認する。
    過去に卵巣腫瘍摘出の手術を受けたことがないか? 白血病などで放射線療法、抗がん薬治療を受けたことがないか?
  1. 自己免疫性疾患、発達異常、脆弱X症候群、X染色体異常の家族歴がないか聴取する。POIの家系内集積の有無も確認する。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

詳しくはクリック
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

著者: C B Coulam, S C Adamson, J F Annegers
雑誌名: Obstet Gynecol. 1986 Apr;67(4):604-6.
Abstract/Text To assess the occurrence of premature ovarian failure, the age-specific incidence rates of natural menopause were determined for a cohort of 1858 women born between 1928 and 1932. These women were identified as Rochester, Minnesota residents in 1950 and were followed for date and type of menopause. A total of nine experienced natural menopause before age 40 years, which represents a 1% risk of natural menopause to age 40. The annual incidence rates of natural menopause per 100,000 person-years were ten for ages 15 to 29 and 76 for ages 30 to 39. In the age group 40 to 44, the incidence of natural menopause increased greatly to 881 per 100,000 person-years at risk.

PMID 3960433  Obstet Gynecol. 1986 Apr;67(4):604-6.
著者: J L Luborsky, P Meyer, M F Sowers, E B Gold, N Santoro
雑誌名: Hum Reprod. 2003 Jan;18(1):199-206.
Abstract/Text BACKGROUND: Premature menopause, also termed premature ovarian failure (POF), is characterized by cessation of menstruation before the age of 40 years. Little information is available on the general prevalence of POF or on the prevalence by ethnic group. There is also a lack of information on the association of POF with health indicators.
METHODS: A cross-sectional survey of women aged 40-55 years was conducted at seven sites in the USA to determine eligibility for a community-based, multi-ethnic longitudinal study of the peri-menopause (The Study of Women Across the Nation, SWAN). Interview data were used to (i). determine the prevalence of self-reported POF overall and by ethnic group, and (ii). assess the association of POF with selected self-reported variables related to health. Cases of POF included only women with no discernible cause for POF.
RESULTS: POF was reported by 1.1% (126/11 652) of women. By ethnicity, 1.0% (95% CI, 0.7-1.4) of Caucasian, 1.4% (95% CI, 1.0-2.1) of African American, 1.4% (95% CI, 0.8-2.5) of Hispanic, 0.5% (95% CI, 0.1-1.9) of Chinese and 0.1% (95% CI, 0.02-1.1) of Japanese women experienced POF. The differences in frequency across ethnic groups were statistically significant (P = 0.01). Only Caucasian, African American and Hispanic women were included in further analyses since too few Asian women had POF. In a multivariate model, POF was independently associated with osteoporosis, female hormone use (excluding oral contraceptives), higher body mass index (BMI) and current smoking after adjustment for education level, ability to pay for basics, site and age at interview. In Caucasian women, use of female hormones, osteoporosis, severe disability and smoking were significantly associated with POF. In contrast, POF in African American women was associated with higher BMI and female hormone use, but not osteoporosis.
CONCLUSIONS: The prevalence of POF appears to vary by ethnicity. Health factors associated with POF also vary by ethnicity but because of the cross-sectional study design, it is not possible to determine cause and effect relationships. Health risks of POF would benefit from further study.

PMID 12525467  Hum Reprod. 2003 Jan;18(1):199-206.
著者: Y M van Kasteren, J Schoemaker
雑誌名: Hum Reprod Update. 1999 Sep-Oct;5(5):483-92.
Abstract/Text Infertility is an important issue for patients with premature ovarian failure (POF). Although oocyte donation offers an alternative method to achieve a pregnancy, many patients seek to reproduce with their own gametes. We performed a literature search to evaluate the possibility of pregnancy following diagnosis, and the additional value of treatment strategies. We found 52 case reports, eight observational studies, nine uncontrolled studies and seven controlled trials. Due to a strong variability in study design, patient selection and mode of intervention, it was not possible to combine the data of the seven studies to perform a meta-analysis. None of the studies showed a statistically significant difference between both (or more) study groups. Due to a lack of incorporation of a placebo group, preference of any treatment over no treatment could not be established. Importantly, the collected data of observational, uncontrolled and controlled studies indicate that POF patients still have a 5-10% chance to conceive following diagnosis. Approximately 80% of the reported pregnancies resulted in the birth of a healthy child. There is no evidence that any treatment can enhance this pregnancy rate.

PMID 10582785  Hum Reprod Update. 1999 Sep-Oct;5(5):483-92.
著者: Emmanuel Kalu, Nick Panay
雑誌名: Gynecol Endocrinol. 2008 May;24(5):273-9. doi: 10.1080/09513590801990764.
Abstract/Text Premature ovarian failure (POF) generally describes a syndrome consisting of amenorrhea, sex steroid deficiency, and elevated/menopausal levels of ganadotropins in a woman aged more than two standard deviations below the mean age at menopause estimated for the reference population. Numerous questions relating to this condition remain unanswered, and several important management issues are yet to be addressed. The challenges posed by this important condition range from difficulties with nomenclature to the absence of standardized diagnostic criteria and management guidelines. In the present paper we discuss the management of spontaneous premature ovarian failure, highlight the challenging issues, review the current literature and propose a practical management outline based on our local practice. Women with POF have unique needs that require special attention. There is an urgent need for a more suitable terminology and evidence-based guidelines on which to establish the diagnosis and manage this difficult condition.

PMID 18569032  Gynecol Endocrinol. 2008 May;24(5):273-9. doi: 10.1080/・・・
著者: Antonio La Marca, Mariangela Pati, Raoul Orvieto, Gaspare Stabile, Alfredo Carducci Artenisio, Annibale Volpe
雑誌名: Fertil Steril. 2006 May;85(5):1547-9. doi: 10.1016/j.fertnstert.2005.10.057. Epub 2006 Apr 17.
Abstract/Text Anti-müllerian hormone (AMH) appears to regulate follicular growth. The aim of this study was to investigate AMH serum levels in patients affected by secondary amenorrhea. The AMH was significantly lower (or undetectable) in patients with premature ovarian failure (POF) and significantly higher in patients affected by polycystic ovary syndrome (PCOS). We suggest that serum AMH evaluation could be associated with that of established hormones, such as FSH, LH, and E2, when the activity of hypothalamo-pituitary-ovarian axis is investigated.

PMID 16616745  Fertil Steril. 2006 May;85(5):1547-9. doi: 10.1016/j.fe・・・
著者: R W Rebar, M I Cedars
雑誌名: Endocrinol Metab Clin North Am. 1992 Mar;21(1):173-91.
Abstract/Text Hypergonadotropic forms of amenorrhea in young women are many and varied, and the disorder is not nearly as uncommon as previously believed. It is likely that all physicians seeing women with amenorrhea will encounter this disorder. Careful evaluation is warranted to eliminate any associated autoimmune disorders. Because of the high likelihood of osteopenia in affected individuals, estrogen replacement therapy is warranted. Although pregnancy is possible in women with secondary hypergonadotropic amenorrhea, remarkably it most commonly occurs in women utilizing exogenous estrogen. Women desirous of achieving a pregnancy are best served by assisted reproductive technology utilizing donor oocytes. Success rates in such patients have been quite high. Thus, physicians today can counsel affected women that pregnancy is indeed possible, even in women with so-called "premature ovarian failure."

PMID 1576980  Endocrinol Metab Clin North Am. 1992 Mar;21(1):173-91.
著者: J Christopher Gallagher
雑誌名: Menopause. 2007 May-Jun;14(3 Pt 2):567-71. doi: 10.1097/gme.0b013e31804c793d.
Abstract/Text OBJECTIVE: To review the data on the effect of early menopause on bone. Do women undergoing early menopause develop lower bone mineral density at an earlier age and do they have a higher incidence of osteoporotic fractures? Is there a difference on bone between women who undergo early natural menopause compared to women who have early menopause after oophorectomy?
RESULTS: The earlier in life that menopause occurs, the lower the bone density will be later in life. Low bone density is associated with a higher fracture rate, and several studies show a relationship between early menopause, oophorectomy, and an increase in osteoporotic fractures.
CONCLUSIONS: Early menopause is a risk factor for osteoporosis. Women with an early menopause should have bone density testing performed within 10 years of menopause so that osteopenia or osteoporosis will be diagnosed early and appropriate anti-resorptive therapy initiated.

PMID 17476146  Menopause. 2007 May-Jun;14(3 Pt 2):567-71. doi: 10.1097・・・
著者: Miriam J J de Kleijn, Yvonne T van der Schouw, André L M Verbeek, Petra H M Peeters, Jan-Dirk Banga, Yolanda van der Graaf
雑誌名: Am J Epidemiol. 2002 Feb 15;155(4):339-45.
Abstract/Text In this study, the authors investigated whether combined information on reproductive factors has additive value to the single reproductive factor age at menopause for assessing endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. They conducted a population-based cohort study that included 9,450 postmenopausal women from Nijmegen, the Netherlands, who were aged 35--65 years at enrollment in 1975, with a median follow-up of 20.5 years. A Cox proportional hazards model and Receiver Operating Curves were used to analyze the data. Women aged 52 years or more at menopause had an 18% reduction in cardiovascular mortality (hazard ratio = 0.82, 95% confidence interval (CI): 0.69, 0.98) compared with those aged 44 years or less. Women with more than 18 years of exposure to endogenous estrogen had a statistically significant 20% reduction in cardiovascular mortality (hazard ratio = 0.80, 95 percent CI: 0.67, 0.96) compared with those who had 13 years of exposure or less. The area under the curve of the Receiver Operating Curves for the two models was identical (area under the curve = 0.67, 95 percent CI: 0.66, 0.68). This study shows that age at menopause is related to cardiovascular disease mortality and that a newly developed composite measure of endogenous estrogen exposure does not add to the predictive value of age at menopause for cardiovascular mortality.

PMID 11836198  Am J Epidemiol. 2002 Feb 15;155(4):339-45.
著者: B K Jacobsen, S F Knutsen, G E Fraser
雑誌名: J Clin Epidemiol. 1999 Apr;52(4):303-7.
Abstract/Text We studied the relationship between age at natural menopause and total mortality as well as mortality from ischemic heart disease in a cohort of 6182 California Seventh-Day Adventist women who reported a natural menopause. During follow-up from 1976 through 1988, there were 1831 deaths. A total of 308 deaths due to ischemic heart disease occurred in women who denied ischemic heart disease at start of follow-up. An early menopause was associated with increased total mortality (P value for linear trend <0.001) and ischemic heart disease mortality (P value for linear trend = 0.03). This relationship could not be explained by possible confounding variables. Our results support the hypothesis that an early natural menopause (35-40 years old) increases the risk of ischemic heart disease. There is, however, also some evidence of increased risk of ischemic heart disease in women with a very late menopause (>55 years), particularly in women who never have used postmenopausal estrogens.

PMID 10235170  J Clin Epidemiol. 1999 Apr;52(4):303-7.
著者: Alison M Mondul, Carmen Rodriguez, Eric J Jacobs, Eugenia E Calle
雑誌名: Am J Epidemiol. 2005 Dec 1;162(11):1089-97. doi: 10.1093/aje/kwi324. Epub 2005 Oct 12.
Abstract/Text Several studies have suggested that a young age at menopause may be associated with increased risk of all-cause mortality. Few studies have examined the influence of age at menopause on specific causes of death other than coronary heart disease. Data from a prospective cohort study of US adults were used to examine the relation between age at natural menopause and all-cause and cause-specific mortality among women who never used hormone replacement therapy, who never smoked, and who experienced natural menopause between the ages of 40 and 54 years. After 20 years of follow-up between 1982 and 2002, 23,067 deaths had occurred among 68,154 women. Results from Cox proportional hazards models showed that all-cause mortality rates were higher among women who reported that menopause occurred at age 40-44 years compared with women who reported that menopause occurred at age 50-54 years (rate ratio (RR) = 1.04, 95% confidence interval (CI): 1.00, 1.08). This increased risk was largely due to higher mortality rates from coronary heart disease (RR = 1.09, 95% CI: 1.00, 1.18), respiratory disease (RR = 1.19, 95% CI: 1.02, 1.39), genitourinary disease (RR = 1.39, 95% CI: 1.07, 1.82), and external causes (RR = 1.56, 95% CI: 1.21, 2.02). These findings suggest that mortality from other diseases, as well as coronary heart disease, may contribute to the increased mortality associated with a younger age at menopause.

PMID 16221806  Am J Epidemiol. 2005 Dec 1;162(11):1089-97. doi: 10.109・・・
著者: Massimo Tartagni, Ettore Cicinelli, Giovanni De Pergola, Maria Antonietta De Salvia, Cristina Lavopa, Giuseppe Loverro
雑誌名: Fertil Steril. 2007 Apr;87(4):858-61. doi: 10.1016/j.fertnstert.2006.08.086. Epub 2007 Jan 29.
Abstract/Text OBJECTIVE: To evaluate the hypothesis that pretreatment with estrogens in women affected by premature ovarian failure (POF) may improve the results of ovarian stimulation.
DESIGN: Double-blind, randomized, placebo-controlled study.
SETTING: Outpatient department in an academic research environment.
PATIENT(S): Fifty women with POF seeking pregnancy.
INTERVENTION(S): Before starting ovarian stimulation, group 1 received 0.05 mg ethinyl-E(2) (EE) three times a day for 2 weeks, while group 2 received placebo. Ovarian stimulation was carried out with recombinant FSH (r-betaFSH), 200 IU/day/SC. Both EE and placebo were administered during ovarian stimulation. Human chorionic gonadotropin (10,000 IU/IM) was added when the follicle exceeded a mean diameter of 18 mm.
MAIN OUTCOME MEASURE: Rate of ovulation in women with POF.
RESULT(S): Levels of FSH before stimulation were significantly lower in group 1 than in group 2. The rate of ovulation in group 1 (8/25; 32%) was significantly higher than in group 2 (0/25; 0%). Notably, induction of ovulation was successful only in patients whose FSH levels after EE treatment were < or =15 mIU/mL.
CONCLUSION(S): Our data suggest that pretreatment with EE improves the success of rate of ovulation induction with exogenous gonadotropins in patients with POF. A threshold of FSH < or =15 mIU/mL should be achieved before starting ovarian stimulation.

PMID 17261285  Fertil Steril. 2007 Apr;87(4):858-61. doi: 10.1016/j.fe・・・
著者: A Badawy, H Goda, A Ragab
雑誌名: Reprod Biomed Online. 2007 Aug;15(2):215-9.
Abstract/Text In this prospective randomized study, women with idiopathic karyotypically normal premature ovarian failure (POF) were treated with gonadotrophin-releasing hormone (GnRH) agonist and gonadotrophins with and without the addition of corticosteroids in an attempt to restore ovarian function. The study comprised 58 women with idiopathic POF randomly allocated to either GnRH agonists (GnRHa) plus gonadotrophin therapy with the addition of corticosteroids (29 patients) or GnRHa plus gonadotrophin therapy with placebo (29 patients). Ovulation occurred in six cases (20.7%) in the dexamethasone group versus three cases (10.3%) in the placebo group. There were two singleton pregnancies in the dexamethasone group. There were no reported complications from the use of dexamethasone apart from a sense of sleepiness and fatigue. The combination of corticosteroids with pituitary suppression followed by ovarian stimulation with gonadotrophin appeared to be beneficial in restoring ovarian function in patients with idiopathic POF and normal karyotype.

PMID 17697500  Reprod Biomed Online. 2007 Aug;15(2):215-9.
著者: Leonidas Mamas, Eudoxia Mamas
雑誌名: Fertil Steril. 2009 Feb;91(2):644-6. doi: 10.1016/j.fertnstert.2007.11.055. Epub 2008 Mar 5.
Abstract/Text Since the first successful birth at our center following treatment with DHEA in a patient with premature ovarian failure (POF), all subsequent patients with POF underwent the same treatment protocol. Receiving very encouraging results (FSH level was decreased in the first five patients and all achieved pregnancy), it was decided to study the action of DHEA for a reasonable length of time and in a larger number of patients to confirm the effectiveness of this particular therapeutic regime.

PMID 18321501  Fertil Steril. 2009 Feb;91(2):644-6. doi: 10.1016/j.fer・・・
著者: Sophie Christin-Maitre
雑誌名: Nat Clin Pract Endocrinol Metab. 2008 Feb;4(2):60-1. doi: 10.1038/ncpendmet0699. Epub 2007 Nov 20.
Abstract/Text
PMID 18030288  Nat Clin Pract Endocrinol Metab. 2008 Feb;4(2):60-1. do・・・

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから