今日の臨床サポート

原発性無月経

著者: 堤治 山王病院

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:2021/08/04
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2020
  1. 日本生殖医学会:生殖医療の必修知識 2020
患者向け説明資料

概要・推奨   

  1. 原発性無月経が疑われる場合、定義上の18歳を待たずに診療を開始する(推奨度1)
  1. 原発性無月経の鑑別には染色体検査が必須である(推奨度1)
  1. 治療にはホルモン療法のみならず、手術を必要とする場合もある(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。
※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:
堤治 : 特に申告事項無し[2022年]
監修:杉野法広 : 研究費・助成金など(浜田市,あすか製薬)[2022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および生殖医療の必修知識2020(日本生殖医学会)に基づき確認を行った。 

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 原発性無月経は定義上18歳を過ぎても月経の開始(初経)をみないものである。
  1. ただし初経年齢が若年化し、平均12歳前後の今日では15歳以上で月経の開始をみないものは原発性無月経に準じた診療の対象となる。
  1. 妊娠や閉経などの生理的無月経を除く病的無月経は発症の時期様式により、原発性無月経と続発性無月経に分類される。婦人科を受診する無月経患者のなかで原発性無月経は数パーセントを占める程度である。
  1. 原因は視床下部、下垂体、卵巣、子宮など多岐にわたり、鑑別診断には局所所見はもちろん、ゴナドトロピンやエストロゲンなどの内分泌検査、染色体検査や遺伝子診断が必要となる。
  1. 治療にはホルモン療法のみならず、性腺摘出など入院手術を必要とすることもある。
  1. 治療により妊娠できるものもあるが、挙児を望めない疾患も含まれる。
 
問診・診察のポイント  
 
  1. 家族歴:原発性無月経の診断に必要な問診の第1は、家族歴である。遺伝性の疾患もあり得るので、家系内に原発性無月経患者ないし月経異常の有無を尋ねる。要領を得ない場合も多いが、結婚歴、子の有無なども聞き、参考にする。兄弟姉妹がある場合は、その二次性徴・女性の場合月経の有無を確認する。

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文献 

A L Herbst, R E Scully, S J Robboy
The significance of adenosis and clear-cell adenocarcinoma of the genital tract in young females.
J Reprod Med. 1975 Jul;15(1):5-11.
Abstract/Text
PMID 1151941
G I SWYER
Male pseudohermaphroditism: a hitherto undescribed form.
Br Med J. 1955 Sep 17;2(4941):709-12.
Abstract/Text
PMID 13250193
V Troche, E Hernandez
Neoplasia arising in dysgenetic gonads.
Obstet Gynecol Surv. 1986 Feb;41(2):74-9.
Abstract/Text We analyzed the clinicopathologic characteristics of 140 cases of neoplasia arising in dysgenetic gonads. These 140 cases were found on a review of the medical literature published between 1953 and 1983. The age of the patients at the time of diagnosis was recorded in 133 patients and ranged from 6 months to 45 years. The mean age at diagnosis was 18 years 8 months. Thirteen (9.8 per cent) patients were below the age of 10 at the time of diagnosis. A menstrual history was recorded in 109 cases. Amenorrhea was present in 103 (94.5 per cent). A Y chromosome or Y-chromosome fragment was present in 90.7 per cent of the 119 patients who had karyotype analysis. Bilateral tumors were found in 54 instances (38.6 per cent). Thus, a total of 194 neoplasms were found. Of these 103 (53.1 per cent) were gonadoblastomas, 38 (19.6 per cent) dysgerminomas, 34 (17.5 per cent), gonadoblastoma with areas of dysgerminoma, and 19 (9.8 per cent) were of other histologic types. Patients with dysgenetic gonads and Y chromosome material are at risk for development of ovarian neoplasm. A dysgerminoma of dysgerminomatous component was present in 37 per cent of the reviewed tumors. These neoplasms have been discovered as early as 6 months of age and 9.8 per cent of the cases occurred in patients below the age of 10. Early exploration and bilateral gonadectomy should be performed in patients with gonadal dysgenesis and Y-chromosome material in their karyotype.

PMID 3005934
Y Takai, O Tsutsumi, I Harada, Y Morita, M Momoeda, Y Fukushima, Y Taketani
A case of XY pure gonadal dysgenesis with 46,XYp-/47,XXYp- karyotype whose gonadoblastoma was removed laparoscopically.
Gynecol Obstet Invest. 2000;50(3):166-9. doi: 10318.
Abstract/Text A case of pure gonadal dysgenesis was investigated. The patient was an 18-year-old Japanese woman with a history of primary amenorrhea. She had poorly developed breasts, a hypoplastic uterus, a normal vagina and infantile genitalia. The patient's karyotype was 46,XYp-/ 47,XXYp-. Microsatellite analysis revealed that the X chromosomes of this patient originated from one of the two maternal X chromosomes. DNA analysis of the Y chromosome revealed that she had a deletion of SRY (the sex-determining region on the Y chromosome). She underwent laparoscopic gonadectomies with a final pathology consistent with gonadoblastoma. Laparoscopic surgery is recommended as it is much less invasive and associated with rapid postoperative recovery.

Copyright 2000 S. Karger AG, Basel
PMID 11014948
R Nakao, M Haji, T Yanase, A Ogo, R Takayanagi, T Katsube, Y Fukumaki, H Nawata
A single amino acid substitution (Met786----Val) in the steroid-binding domain of human androgen receptor leads to complete androgen insensitivity syndrome.
J Clin Endocrinol Metab. 1992 May;74(5):1152-7. doi: 10.1210/jcem.74.5.1569163.
Abstract/Text Androgen receptors (ARs) in two Japanese siblings with complete androgen insensitivity syndrome were characterized, and their molecular bases were investigated. Androgen binding was undetectable in cultured pubic skin fibroblasts from the patients by whole cell assay. Sequence analysis of exons B-H, which encode the DNA- and steroid-binding domains, of the AR gene from these patients using polymerase chain reaction revealed a single nucleotide substitution in exon F, resulting in an amino acid change at 786 from methionine (ATG) to valine (GTG) within the steroid-binding domain of AR. Reconstruction of this mutation by site-directed mutagenesis into human AR cDNA followed by expression in COS-1 cells led to production of the same amount and the same molecular mass of immunodetectable AR protein as those found with expression of the normal human AR cDNA. However, in contrast to wild-type AR expressed in COS-1 cells, the mutant AR showed markedly low affinity of androgen binding by whole cell assay. These results suggest that androgen resistance in these patients is due to the point mutation in the steroid-binding domain of the AR.

PMID 1569163
L S Levine, M Zachmann, M I New, A Prader, M S Pollack, G J O'Neill, S Y Yang, S E Oberfield, B Dupont
Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group.
N Engl J Med. 1978 Oct 26;299(17):911-5. doi: 10.1056/NEJM197810262991702.
Abstract/Text To document further the proposed genetic linkage between congenital adrenal hyperplasia due to 21-hydroxylase deficiency and HLA, 34 unrelated families from New York and Zurich, with a total of 48 patients, 48 siblings and their parents, were studied. All patients were HLA genotypically different from the healthy sibs; when two or more children were affected in the same sibship they were always HLA-B identical. The gene for 21-hydroxylase deficiency was separated by genetic recombination from the HLA-A locus and from the locus for glyoxalase I-polymorphism. No HLA-A, HLA-B or HLA-C antigen was selectively increased among the 34 unrelated patients. Lod-score analysis for HLA-B:21-hydroxylase deficiency gave a peak for theta approximately 0.00 at 5.20 for females and 4.30 for males, giving a total peak lod score of 9.5 at theta approximately 0.00 when male and female lod scores were combined. Close genetic linkage between HLA-B and 21-hydroxylase deficiency was thus established.

PMID 692595
Abstract/Text Vaginal agenesis combined with a functional uterus is a rare condition in which treatment modalities that preserve reproductive function are controversial. A 21 year old female presented with congenital vaginal agenesis combined with cervical atresia. She was treated with gonadotrophin-releasing hormone (GnRH) agonists for a total period of over 5 years when a non-functioning pituitary tumour was detected by brain magnetic resonance imaging (MRI). A laparoscopically assisted reconstruction of a neovagina and neoendocervical canal was performed utilizing lyophilized porcine dermal skin to line the neovagina. Endometriosis of the pelvis was revealed and adhesiolysis and cauterization were also carried out under laparoscopy. The GnRH agonist was discontinued and the patient resumed cyclic menses with no abdominal pain. The pituitary tumour decreased in size 6 months after the cessation of GnRH agonists. We raise the question as to whether pituitary MRI should be performed for patients who need long-term administration of GnRH agonists.

PMID 10528004
M V Sauer, R A Lobo, R J Paulson
Successful twin pregnancy after embryo donation to a patient with XY gonadal dysgenesis.
Am J Obstet Gynecol. 1989 Aug;161(2):380-1.
Abstract/Text A twin pregnancy was established in a patient with XY gonadal dysgenesis. The pregnancy was supported with exogenously administered hormones for the initial 100 days. The infants were delivered by emergency cesarean section at 35 weeks' gestation when severe preeclampsia developed in the mother.

PMID 2764056
Mats Brännström, Liza Johannesson, Hans Bokström, Niclas Kvarnström, Johan Mölne, Pernilla Dahm-Kähler, Anders Enskog, Milan Milenkovic, Jana Ekberg, Cesar Diaz-Garcia, Markus Gäbel, Ash Hanafy, Henrik Hagberg, Michael Olausson, Lars Nilsson
Livebirth after uterus transplantation.
Lancet. 2015 Feb 14;385(9968):607-16. doi: 10.1016/S0140-6736(14)61728-1. Epub 2014 Oct 6.
Abstract/Text BACKGROUND: Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported.
METHODS: In 2013, a 35-year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden. The uterus was donated from a living, 61-year-old, two-parous woman. In-vitro fertilisation treatment of the recipient and her partner had been done before transplantation, from which 11 embryos were cryopreserved.
FINDINGS: The recipient and the donor had essentially uneventful postoperative recoveries. The recipient's first menstruation occurred 43 days after transplantation and she continued to menstruate at regular intervals of between 26 and 36 days (median 32 days). 1 year after transplantation, the recipient underwent her first single embryo transfer, which resulted in pregnancy. She was then given triple immunosuppression (tacrolimus, azathioprine, and corticosteroids), which was continued throughout pregnancy. She had three episodes of mild rejection, one of which occurred during pregnancy. These episodes were all reversed by corticosteroid treatment. Fetal growth parameters and blood flows of the uterine arteries and umbilical cord were normal throughout pregnancy. The patient was admitted with pre-eclampsia at 31 full weeks and 5 days, and 16 h later a caesarean section was done because of abnormal cardiotocography. A male baby with a normal birthweight for gestational age (1775 g) and with APGAR scores 9, 9, 10 was born.
INTERPRETATION: We describe the first livebirth after uterus transplantation. This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility. Furthermore, the results show the feasibility of live uterus donation, even from a postmenopausal donor.
FUNDING: Jane and Dan Olsson Foundation for Science.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 25301505

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