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無症候性副腎腫瘤

著者: 尾田琢也 松尾小児科医院

監修: 野口善令 豊田地域医療センター 総合診療科

著者校正/監修レビュー済:2021/11/17
参考ガイドライン:
  1. 欧州内分泌学会のManagement of adrenal incidentalomas:European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors
患者向け説明資料

概要・推奨   

  1. 無症候性副腎腫瘤、または、副腎偶発腫(adrenal incidentaloma)とは画像検査で偶然にみつかった症状のない副腎腫瘤を指す 。
  1. 副腎偶発腫の多くは、非機能性で良性の副腎皮質由来の腺腫であるが、機能性(ホルモン産生性)、悪性のものもみられる。
  1. 副腎偶発腫をみたときは、機能性、悪性の可能性の評価を行う(推奨度1)。
  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。閲覧にはご契約が必要
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:
尾田琢也 : 特に申告事項無し[2021年]
監修:野口善令 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、疫学情報、評価アルゴリズムについて加筆修正を行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 無症候性副腎腫瘤は、副腎偶発腫(adrenal incidentaloma)とも呼ばれ、副腎疾患以外の評価目的で行われた画像検査で偶然にみつかった径が1cm以上の症状のない副腎腫瘤をいう[1]
  1. 剖検例の6%(1~32%)[1][2]、腹部CT検査の4%程度[3]でみられ、年齢とともに増加する。約75%の副腎腫瘤は、非機能性で良性の副腎皮質由来の腺腫である。12%がサブクリニカルクッシング症候群、7.0%が褐色細胞腫、2.5%がアルドステロン症、8.0%が副腎皮質癌、5.0%が転移性腫瘍である[4]
  1. 副腎偶発腫をみたときは、機能性かどうか、悪性の可能性があるかどうかに注意を払い、以下の疾患を考慮する。
 
  1. サブクリニカルクッシング症候群:典型的な副腎皮質機能亢進の症状や徴候がないが、コルチゾールの自動分泌がみられるものをさす。クッシング症候群の典型的な像は呈さないが、高血圧、肥満、糖尿病、骨粗鬆症がみられることがある。副腎偶発腫の12%にコルチゾールの自動分泌があったという報告があり[4]、副腎偶発腫の全例で一晩1mgデキサメタゾン抑制試験が必要である。一晩1mgデキサメタゾン抑制試験で翌朝8時のコルチゾール値が5μg/dL以上であれば、自動分泌能ありと判断される[5][6]。カットオフ値は議論中であるが、臨床的に意義のあるグルココルチコイドの自動分泌能の基準として5μg/dLが妥当と考えられている。検査特異度は91%[7][8]であるため、異常な結果が出た場合は、偽陽性を除外するために確定診断が必要である。1.8~5.0μg/dLの場合は、慎重に経過をフォローアップするか、副腎性サブクリニカルクッシング症候群新診断基準診断アルゴリズムを参考に精査を行う。血漿ACTH、デヒドロエピアンドロステロンサルフェート(DHEAS)、尿中遊離コルチゾールが測定されることがある。血漿ACTHの抑制、デヒドロエピアンドロステロンサルフェート(DHEAS)の抑制、尿中遊離コルチゾールが基準値の4倍以上がコルチゾールの過剰分泌を示唆する[9]。副腎偶発腫の診断後、4年以上の経過観察中にコルチゾールの自動分泌が確認されたという報告が少なくとも2つ[10][11]あるため、4年間は毎年、コルチゾールの過剰分泌があるかどうか内分泌検査を施行するように勧められることが多い。
 
副腎性サブクリニカルクッシング症候群新診断基準 診断アルゴリズム

CS:クッシング症候群
DST:1mg dexamethasone抑制試験、数字は血中コルチゾール値(μg/dL)
ACTH分泌抑制:血中ACTH<10pg/mLまたはCRH負荷に対する低反応(<1.5倍)
日内リズム消失:21~24時血中コルチゾール≧5μg/dL

 
  1. 副腎偶発腫の精査でサブクリニカルクッシング症候群と診断された場合は、腹腔鏡下での副腎切除術が勧められる(推奨度2R)。(参考文献:[12]
  1. サブクリニカルクッシング症候群の患者の治療方針として外科的治療を行うか、経過観察するかどうかに関しての前向き比較試験が1つある。25年の期間で、サブクリニカルクッシング症候群の患者45人を無作為に手術群23人、経過観察群22人に割り付けた。外科的手術はすべて同一術者により腹腔鏡下で施行された。経験のある内分泌科医師により術後6カ月後と12カ月後に、その後は年1回、中央値で7.7年間(2~17年間)観察された。手術群では、糖尿病患者の62.5%、高血圧患者の67%、脂質異常症の37.5%、肥満患者の50%で疾患が正常化または改善した。骨粗鬆症患者の骨マーカーは変化なかった。一方、経過観察群では、糖尿病、高血圧、脂質異常症が悪化したものがいた。
 
  1. 無症候性褐色細胞腫:副腎偶発腫の7.0%を占める[4]。褐色細胞腫の58%は副腎偶発腫から診断され、19人中に10人にしか高血圧がみられなかったとする報告がある[13]。無症候性の褐色細胞腫であっても致死的となることがあるので注意が必要である。褐色細胞腫かどうかについては、副腎偶発腫の画像的特徴が参考になる。単純CT検査での吸収値上昇、造影CT検査での豊富な血流、造影剤のwash-out遅延、T2強調MRIで高信号を呈するなどが特徴である。すべての褐色細胞腫がこのような画像所見をとるわけではないので、副腎偶発腫の全例で内分泌検査が必要である。24時間蓄尿におけるメタネフリン分画およびカテコラミンの測定が推奨される。感度・特異度とも高く、91~98%と報告されている[14][15][16]。基準値上限のおおよそ3倍以上で疑い、確定診断が必要である。蓄尿検査を行う前に随時尿でのスクリーニングも有用である。随時尿メタネフリンもしくはノルメタネフリンが500ng/mgCrを超える場合は、褐色細胞腫の可能性が高い[17]
  1. 原発性アルドステロン症:副腎偶発腫の2.5%を占める[4]。アルドステロンの過剰分泌は心血管系疾患のリスクを増加させる。副腎偶発腫の患者で高血圧や低カリウム血症がある場合は、アルドステロンの過剰分泌があるかどうかを調べる必要がある。スクリーニングとして血清K値は参考にならない。早朝座位での血漿アルドステロン(ng/dL)/レニン活性(ng/mL/時)>20かつ血漿アルドステロン>15ng/dLであれば、確定診断が必要である。
  1. 悪性かどうかの判断に関しては、腫瘤径と腫瘤の画像的特徴の2つが主要な予測因子となる。副腎偶発腫のうち、副腎皮質癌と転移性副腎腫瘍が占めるのは、それぞれ8.0%、5.0%であったという報告がある[4]
  1. 腫瘤径:径が4cmを超えれば、副腎皮質癌の感度は90%であるが、特異度は24%と低い[18]。4cm未満の副腎皮質癌も報告[19]されているため、絶対的に安全な腫瘍径のカットオフ値は存在しない。良性の無症候性副腎腫瘤が40歳未満で発症することはまれであるため、この年齢層なら4cm未満であっても癌の可能性を検討する必要がある[20]。径が6cmを超えるものは切除を勧める専門家が多い[21]が、手術に関しては、腫瘤の画像的特徴、年齢、合併症などを考慮して判断する必要がある。腫瘍径を計測する際に重要なことは、三次元で最大径を評価することである。二次元の断面のみで計測すると過小評価することが多い[20]
  1. 画像的特徴:腺腫であれば、脂質に富むことが多いため、単純CT検査で低吸収となる[22]。既知の悪性腫瘍がない場合は、単純CT検査での吸収値が10Hounsfield単位以下であれば良性である[23]。ただし、30%の腺腫はそれほど脂質を含まず、単純CT検査で非腺腫と鑑別することは難しい。腺腫では、造影CT検査で造影剤の早期wash-outがみられる[24]。造影剤投与10分後のwash-out率が40~60%を超える場合、副腎癌、褐色細胞腫、転移性腫瘍の患者と比較して、腺腫の感度・特異度が100%であったという報告がある[22][24]
  1. ケミカルシフトMRI検査の逆位相において信号低下がみられれば、腺腫の可能性が高い。18F-FDG PET-CT副腎画像のSUVmaxや副腎/脾SUVmax比もしくは副腎/肝臓SUVmax比が良性悪性の鑑別に利用できる。
  1. 副腎皮質癌:副腎偶発腫の8.0%である[4]。まれだが、予後は不良である。初診時の腫瘍ステージと根治的切除が可能かどうかにより長期生存率が決まる。2/3は機能性であり、過剰ホルモンによる症状が出る。
  1. 転移性腫瘍:悪性腫瘍の病歴がある患者の約半数では、転移性腫瘍である[25]。この場合は、両側性のことが多い。原発巣として、肺、腎、大腸、乳腺、食道、膵、肝臓、胃が多く[26]、転移性副腎腫瘍が原発巣より先にみつかることはきわめてまれである[27]
  1. 微細針生検:細胞診では、副腎癌と腺腫の区別は困難であり、生検の目的は腫瘤が副腎組織かそうでないかを区別することである[28][29][30]。褐色細胞腫であった場合は、出血や高血圧緊急症などの合併症が起こり得るので、生検前に血液検査で褐色細胞腫を除外する必要がある[31][32]。転移性腫瘍や感染か疑われる場合は、褐色細胞腫を除外して、微細針生検を検討する。
  1. 両側副腎腫瘤:副腎偶発腫の15%でみられる[18][10]。原発性両側性大結節性副腎過形成、副腎腺腫、両側性褐色細胞腫、先天性副腎皮質過形成、クッシング病もしくは異所性ACTH分泌による両側性副腎皮質過形成、転移性腫瘍、原発性腫瘍、副腎骨髄脂肪腫、感染、出血、グルココルチコイド抵抗症などが鑑別疾患として挙がる[20]
  1. 副腎偶発腫のフォローアップについて、適切な頻度や期間ははっきりしていない。通常は、6カ月後、12カ月後、24カ月後の画像検査が推奨される。悪性腫瘍であれば、3カ月で増大することが多いので、画像所見から悪性が疑われる場合は、3カ月後など、より早期のフォローアップが妥当かもしれない[33]。最初の検査に異常がなくても、その後に異常となることがあるので、最初の4年間は年に1回、カテコラミンとコルチゾールの過剰分泌があるかどうか内分泌検査を施行するように勧められている[21]。経過中にアルドステロン症と診断されたという報告はないため、アルドステロン症のスクリーニングは不要である。
問診・診察のポイント  
  1. 副腎機能亢進症や悪性疾患を示唆する症状や所見に焦点を絞って病歴聴取、身体所見をとる[33]
 
問診:
  1. クッシング症候群:体重増加、中心性肥満、満月様顔貌、水牛様脂肪沈着、皮下出血、皮膚脆弱・菲薄化、創傷治癒遷延、赤紫色皮膚線条、近位筋筋力低下、感情や認知機能の変化(イライラ、感情失禁、抑うつ気分、落ち着きのなさ)、日和見感染、真菌感染、性機能障害、ざ瘡、多毛症
  1. 褐色細胞腫:動悸、顔面蒼白、振戦、発汗、失神。症状は発作的にみられることもある。安静時や、姿勢変化、不安、薬剤(例:メトクロプラミド、麻酔薬)、腹圧を増加させる運動(姿勢変化、重いものを持ち上げる作業、排便、運動、大腸内視鏡検査、妊娠、外傷)などを契機に生じる。
  1. 原発性アルドステロン症:低カリウム血症があれば、夜間尿、多尿、筋けいれん、動悸
  1. 副腎皮質癌:腫瘍そのものによる圧迫症状(腹痛など)、コルチゾール分泌過剰症状(クッシング症候群)、アンドロゲン過剰症状(多毛症、ざ瘡、無月経や過少月経、脂ぎった皮膚、リビドー亢進)、エストロゲン過剰症状(女性化乳房など)、アルドステロン過剰症状(低カリウム血症に関連した症状)
  1. 転移性腫瘍:副腎以外の悪性腫瘍の病歴
 
診察:
  1. クッシング症候群:高血圧、骨塩減少、骨粗鬆症、食後高血糖、糖尿病、低カリウム血症、脂質異常症、白血球増多、リンパ球減少
  1. 褐色細胞腫:高血圧(一時的のことも持続的のこともある)、起立性低血圧、顔面蒼白、網膜症、振戦、発熱
  1. 原発性アルドステロン症:高血圧症、低カリウム血症、軽度の高ナトリウム血症
  1. 副腎皮質癌:高血圧、骨塩減少、骨粗鬆症、食後高血糖、糖尿病、低カリウム血症、脂質異常症、白血球増多、リンパ球減少
  1. 転移性腫瘍:各悪性腫瘍に特異的な所見
 
鑑別疾患表:
機能性腫瘍
  1. 腺腫(アルドステロンまたはコルチゾール)

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文献 

著者: W F Young
雑誌名: Endocrinol Metab Clin North Am. 2000 Mar;29(1):159-85, x.
Abstract/Text Two biproducts of the revolution in diagnostic imaging techniques are unintended discoveries, and uncertainty for the patient and the clinician. To address the uncertainty associated with adrenal incidentalomas, clinicians need to understand the definition, differential diagnosis, and options for assessment with respect to functional status and malignancy potential. This article presents an algorithmic approach that addresses these issues.

PMID 10732270  Endocrinol Metab Clin North Am. 2000 Mar;29(1):159-85, ・・・
著者: R T Kloos, M D Gross, I R Francis, M Korobkin, B Shapiro
雑誌名: Endocr Rev. 1995 Aug;16(4):460-84. doi: 10.1210/edrv-16-4-460.
Abstract/Text Independently, endocrinology, radiology, and nuclear medicine can not optimally differentiate the etiology of the incidental adrenal mass. Rather, the insight necessary for this task must be contributed by all three disciplines. Incidentally discovered adrenal masses are being detected at an increasing rate. This trend is expected to continue based on the incidence of adrenal masses in autopsy series and the increasing use of high resolution abdominal imaging techniques. CT and MRI are able to definitely characterize only a minority of these lesions (simple cyst, myelolipoma, obvious local malignant invasion). Biochemical screening for hormone excess is essential regardless of a nonsuggestive complete history and physical examination. An argument may be made for not further pursuing nonhypersecreting lesions with the typical features of a benign adenoma on CT scan and an attenuation value of 0 HU or less. Adrenocortical scintigraphy is recommended in all patients with normal biochemical screening tests, especially those with CT attenuation values greater than 0 HU. In this setting, we believe that the functional and anatomical information provided by NP-59 and [75Se]selenomethylnorcholesterol scintigraphy allows one to noninvasively, accurately, and less expensively (Table 9) categorize adrenal masses as benign nonhypersecretory adenomas (the vast majority) vs. a possibly malignant lesion (the minority). In the presence of normal biochemistry, a concordant NP-59 imaging pattern is diagnostic of a nonhypersecretory benign adrenal adenoma and requires no immediate therapeutic intervention. Conversely, patients with discordant patterns of NP-59 scintigraphy have lesions that carry a significant risk for malignancy, and the pursuit of a tissue diagnosis is indicated, usually by means of FNA. Normal adrenocortical tissue on cytological studies in this setting may represent inadvertent sampling of adjacent normal adrenocortical tissues or the presence of a well differentiated adrenocortical carcinoma. In patients with lesions larger than 2 cm in whom NP-59 scintigraphy is nonlateralizing, the possibility of a periadrenal or pseudoadrenal mass is likely and should prompt review, or perhaps even repeat, of high resolution adrenal imaging (occasionally angiography may be helpful). In lesions shown to be 2 cm or less in size with a nonlateralizing NP-59-scan, there is a possibility of a periadrenal or pseudoadrenal mass; however, once this is excluded it must be recognized that benign and malignant lesions, because of the limitations of scintigraphy, cannot always be clearly distinguished by this method when masses are small.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID 8521790  Endocr Rev. 1995 Aug;16(4):460-84. doi: 10.1210/edrv-16・・・
著者: S Bovio, A Cataldi, G Reimondo, P Sperone, S Novello, A Berruti, P Borasio, C Fava, L Dogliotti, G V Scagliotti, A Angeli, M Terzolo
雑誌名: J Endocrinol Invest. 2006 Apr;29(4):298-302.
Abstract/Text Adrenal incidentalomas, defined as masses discovered incidentally during imaging investigation of non-adrenal disorders, have become a rather common finding in clinical practice. The prevalence is not well characterized and varies among studies. The aim of the present study was to perform a prospective evaluation of the prevalence of adrenal incidentalomas among subjects undergoing computerized tomography (CT) scan of the chest in a screening program of lung cancer (Tic TAC study) in Piedmont, a region of Northwestern Italy. This evaluation included 520 subjects (382 males and 138 females, aged between 55-82 yr), referred to our hospital from April to December 2001. Twenty-three patients with adrenal masses were identified: 21 adrenal adenomas, 1 myelolipoma, and 1 metastasis of lung cancer. Therefore, the overall prevalence of adrenal lesions was 4.4%, and that of benign adrenal masses was 4.2%. This prevalence is higher than those found in previous CT scan series reported in the literature, probably because of the use of high-resolution CT scanning technology. Another factor that influenced our results is that subject age is skewed towards the decades characterized by a greater occurrence of adrenal masses. The outcome of this study confirms that we are presently able to identify incidentally discovered adrenal masses more often than in early years and that the prevalence of adrenal incidentalomas on CT images is approaching that of autopsy series. The present study provides a reliable estimate of the prevalence of adrenal incidentaloma with currently used CT scanners. Notwithstanding that our subjects were at increased risk of lung cancer, the rate of adrenal metastases was low. We think that the present results can be generalized even if we may disclose the lack of histological diagnosis.

PMID 16699294  J Endocrinol Invest. 2006 Apr;29(4):298-302.
著者: Martin Fassnacht, Wiebke Arlt, Irina Bancos, Henning Dralle, John Newell-Price, Anju Sahdev, Antoine Tabarin, Massimo Terzolo, Stylianos Tsagarakis, Olaf M Dekkers
雑誌名: Eur J Endocrinol. 2016 Aug;175(2):G1-G34. doi: 10.1530/EJE-16-0467.
Abstract/Text : By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with 'autonomous cortisol secretion' who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas.

© 2016 European Society of Endocrinology.
PMID 27390021  Eur J Endocrinol. 2016 Aug;175(2):G1-G34. doi: 10.1530/・・・
著者: C A NUGENT, T NICHOLS, F H TYLER
雑誌名: Arch Intern Med. 1965 Aug;116:172-6.
Abstract/Text
PMID 14315650  Arch Intern Med. 1965 Aug;116:172-6.
著者: S Tsagarakis, D Vassiliadi, N Thalassinos
雑誌名: J Endocrinol Invest. 2006 May;29(5):471-82.
Abstract/Text Subclinical hypercortisolism (SH) is a newly characterized hormonal disorder that is almost exclusively detected in the context of incidentally discovered adrenal masses. The diagnostic criteria used for the definition of this condition are at present controversial. Amongst the various tests used for the detection of this abnormality (dexamethasone suppression, urinary free cortisol, ACTH levels, midnight serum or salivary cortisol concentrations, ACTH responses to CRH stimulation), the dexamethasone suppression tests (DST) seem to better accomplish the task of unmasking subtle abnormalities of cortisol secretion. Several versions of DST have been used: the 1-mg overnight, the 3-mg overnight and the classical 2-day low-dose DST. This latter test has the theoretical advantage that, by more efficiently suppressing pituitary ACTH secretion, it may provide a measure of the residual (ie non- ACTH-dependent) cortisol secretion from the adrenal mass. In this way, post-dexamethasone cortisol concentrations may quantify the degree of autonomous cortisol hypersecretion. In fact, post-dexamethasone cortisol concentrations have a negative correlation with basal ACTH levels and a positive correlation with midnight cortisol concentrations as well as the size of the incidentally discovered adrenal mass. Most of the existing data indicate that SH detected in the context of adrenal incidentalomas may have some clinically significant implications. In fact, patients with higher post-dexamethasone cortisol concentrations demonstrate higher lipid levels and lower bone mass densities. It has also been suggested that SH may be responsible for biochemical and phenotypic changes reminiscent of the metabolic syndrome. In summary, SH does exist and is associated with a negative impact in patients' health; however, hormonal cut-off criteria for decision-making remain to be defined.

PMID 16794373  J Endocrinol Invest. 2006 May;29(5):471-82.
著者: S Tsagarakis, C Roboti, P Kokkoris, V Vasiliou, C Alevizaki, N Thalassinos
雑誌名: Clin Endocrinol (Oxf). 1998 Aug;49(2):165-71.
Abstract/Text OBJECTIVE: It has recently been suggested that autonomous cortisol production may lead to subclinical glucocorticoid excess in a substantial number of patients with incidentally discovered adrenocortical adenomas. Following a standard low-dose dexamethasone suppression test (LDDST) cortisol concentrations are frequently incompletely suppressed in patients with adrenal incidentalomas, due to an ACTH-independent secretion of cortisol by the adrenal mass. Thus, post LDDST cortisol concentrations may provide a measure of the degree of autonomous glucocorticoid secretion, but hormonal alterations in relation to post-LDDST cortisol concentrations have not been thoroughly investigated.
PATIENTS AND MEASUREMENTS: 61 patients with radiological features highly suggestive of adrenal adenomas were studied. These included 43 women, 18 men; mean age 59 +/- 1.4, range: 25-76 years; BMI 30.9 +/- 0.8 kg/m2 and waist:hip ratio 0.90 +/- 0.016. All subjects underwent a standard LDDST, as follows: after a 48-hr stabilisation period, 24-hr urine collections for basal urinary free cortisol (UFC) were performed. Basal serum cortisol and plasma ACTH were measured at 8 AM and at midnight the following day, and subjects started dexamethasone 0.5 mg 6 hourly for 2 days. Post-dexamethasone cortisol and ACTH levels were measured at 8 AM, 6-hrs after the last dose of dexamethasone. Blood samples for dehydroepiandrosterone sulphate (DHEAS) and serum lipids were obtained on the morning preceding dexamethasone administration.
RESULTS: Post-LDDST cortisol concentrations correlated positively with the size of the adenoma (r = +0.527, P < 0.001). There was a negative rank correlation of post-LDDST cortisol concentrations and basal ACTH levels at 0900 h (rs = -0.426, P < 0.001) and DHEAS (rs = -0.380, P = 0.006). Moreover, there was a good rank correlation between DHEAS and basal ACTH levels (rs = +0.456, P < 0.001). A positive rank correlation was observed between post-LDDST cortisol concentrations and midnight cortisol concentrations (rs = +0.317, P = 0.020). As recent studies have suggested that post-LDDST cortisol levels higher than 70 nmol/l may indicate significant hypercortisolism comparisons were also performed between patients divided according to post-LDDST cortisol values into 3 groups: Group A, > 70 nmol/l (19 pts); Group B, 30-70 nmol/l (27 pts); Group C, < 30 nmol/l (15 pts). Although there was no difference in basal cortisol and UFC values between these groups, ACTH and DHEAS levels were significantly lower, and midnight cortisol significantly higher in group A compared to group C patients (P = 0.030, P = 0.017 and P = 0.001 respectively). Cholesterol and triglyceride levels were slightly albeit significantly higher in group A compared to group C patients (P < 0.05).
CONCLUSIONS: It is concluded that higher post-low dose dexamethasone cortisol concentrations are associated with lower ACTH and dehydroepiandrosterone sulphate, higher midnight cortisol concentrations and larger adenomas. These findings are consistent with the hypothesis that post-low dose dexamethasone cortisol concentrations represent a useful index in assessing subtle glucocorticoid autonomy in patients with adrenal adenomas.

PMID 9828902  Clin Endocrinol (Oxf). 1998 Aug;49(2):165-71.
著者: R Görges, G Knappe, H Gerl, M Ventz, F Stahl
雑誌名: J Endocrinol Invest. 1999 Apr;22(4):241-9.
Abstract/Text We studied plasma cortisol levels at 00:00 h and 08:00 h in 103 patients with Cushing's syndrome and 144 patients in whom this diagnosis had been excluded. These patients were hospitalized in our department from 1975 to 1996. Additionally, we measured these parameters in 20 healthy volunteers and in 5 patients with nonendocrine disease. Corresponding data of urinary free cortisol and low-dose dexamethasone suppression testing were included in the evaluation. Values (mean+/-SD) from patients with Cushing's syndrome: 510+/-232 nmol/l (range 165-1488) for plasma cortisol 00:00 h, 574+/-242 nmol/l (range 236-1612) for plasma cortisol 08:00 h, 991+/-885 nmol/24 h (range 154-4866) for urinary free cortisol and 479+/-304 nmol/l (range 34 - 1,393) for plasma cortisol after 1.5 mg dexamethasone. Values from the patients excluded from Cushing's syndrome: 99+/-76 nmol/l (range 5-371) for plasma cortisol 00:00 h, 393+/-136 nmol/l (range 119-812) for plasma cortisol 08:00 h, 126+/-84 nmol/24 h (range 30-485) for urinary free cortisol, and 64+/-82 nmol/l (range 5-395) for plasma cortisol after 1.5 mg dexamethasone. Values of the healthy volunteers respectively patients with non-endocrine disease: 59+/-30 nmol/l (range 25-130) respectively 127+/-80 nmol/l (range 62-265) for plasma cortisol 00:00 h and 388+/-144 nmol/l (range 157-651) respectively 498+/-113 nmol/l (range 302-581) for plasma cortisol 08:00 h. None of the Cushing patients exhibited a 00:00 h plasma cortisol below 140 nmol/l and only one had a urinary free cortisol below 200 nmol/24 h, whereas 4 were complete dexamethasone suppressors. The diagnostic value of these parameters was examined based on various cutoffs. We recommend determination of midnight plasma cortisol as an efficient and simple additional procedure for the diagnosis of Cushing's syndrome. The sensitivity and specificity of this procedure is similar to urinary free cortisol and slightly above the low-dose dexamethasone suppression testing in our hospitalized patients.

PMID 10342356  J Endocrinol Invest. 1999 Apr;22(4):241-9.
著者: G Arnaldi, A Angeli, A B Atkinson, X Bertagna, F Cavagnini, G P Chrousos, G A Fava, J W Findling, R C Gaillard, A B Grossman, B Kola, A Lacroix, T Mancini, F Mantero, J Newell-Price, L K Nieman, N Sonino, M L Vance, A Giustina, M Boscaro
雑誌名: J Clin Endocrinol Metab. 2003 Dec;88(12):5593-602. doi: 10.1210/jc.2003-030871.
Abstract/Text In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

PMID 14671138  J Clin Endocrinol Metab. 2003 Dec;88(12):5593-602. doi:・・・
著者: Luisa Barzon, Francesco Fallo, Nicoletta Sonino, Marco Boscaro
雑誌名: Eur J Endocrinol. 2002 Jan;146(1):61-6.
Abstract/Text OBJECTIVE: The natural course of adrenal incidentalomas, especially those with subclinical autonomous glucocorticoid production, i.e. subclinical Cushing's syndrome, and the risk that such conditions will evolve towards overt Cushing's syndrome are unknown.
DESIGN: Longitudinal follow-up evaluation of a series of 284 consecutive patients with adrenal incidentaloma.
METHODS AND RESULTS: Out of 284 consecutive patients with adrenal incidentaloma studied at our Institution in the last 15 years, 98 patients (23 with subclinical hypercortisolism) underwent surgery. Of 130 non-operated patients with a follow-up of at least 1 year, eight had subclinical hypercortisolism at diagnosis. We describe in detail four patients who developed overt Cushing's syndrome after 1-3 years of follow-up. Only one of these patients had subclinical hypercortisolism at first diagnosis. Estimated cumulative risk for a non-secreting adrenal incidentaloma to develop subclinical hyperfunction was 3.8% after 1 year and 6.6% after 5 years. For patients with masses with subclinical autonomous glucocorticoid overproduction, estimated cumulative risk to develop overt Cushing's syndrome was 12.5% after 1 year.
CONCLUSIONS: In patients with adrenal incidentalomas the risk of progression towards overt Cushing's syndrome is not low, at variance with previous reports. A careful biochemical and hormonal follow-up is advisable in all patients who do not need surgery at first presentation.

PMID 11751069  Eur J Endocrinol. 2002 Jan;146(1):61-6.
著者: O C C Will, A Hansmann, R K S Phillips, F F Palazzo, K Meeran, M Marshall, S K Clark
雑誌名: Dis Colon Rectum. 2009 Sep;52(9):1637-44. doi: 10.1007/DCR.0b013e3181a876d6.
Abstract/Text PURPOSE: Adrenal incidentaloma is often diagnosed in patients with familial adenomatous polyposis, because they frequently undergo abdominal imaging and have a raised incidence of adrenal incidentaloma. This study investigates the natural history of adrenal incidentaloma in familial adenomatous polyposis, and suggests a schema for management.
METHODS: An original cohort of 14 familial adenomatous polyposis patients with adrenal incidentaloma, identified prospectively 12 years ago, was followed up clinically and radiologically. A further group of 16 patients was also identified. All had lesions >1 cm. For both cohorts, characteristics of patients (genotype, age at diagnosis, concomitant diagnoses) and incidentaloma (size, laterality, rate of growth, outcome) are described.
RESULTS: Overall, 3 of 30 patients underwent adrenalectomy; one patient had pheochromocytoma and another had an adenoma of borderline malignancy. A further three lesions were radiologically suspicious for malignancy at the time of diagnosis; one was in a patient who was unfit for surgery but died of nonadrenal causes after nine years. None of the lesions radiologically benign at diagnosis showed an aggressive course, but one patient required referral for surgery after 12 years because of a slow increase in size of the lesion. There were no associations with genotype.
CONCLUSIONS: Familial adenomatous polyposis-associated adrenal incidentaloma may warrant long-term follow-up. Although the natural history is similar to lesions occurring sporadically, these patients have concomitant familial adenomatous polyposis-associated manifestations under radiologic surveillance. In this rare condition, development of a robust protocol will require evidence from worldwide patient cohorts. However, a tailored schema is suggested as a consistent basis for future modification.

PMID 19690494  Dis Colon Rectum. 2009 Sep;52(9):1637-44. doi: 10.1007/・・・
著者: Antonio Toniato, Isabella Merante-Boschin, Giuseppe Opocher, Maria R Pelizzo, Francesca Schiavi, Enzo Ballotta
雑誌名: Ann Surg. 2009 Mar;249(3):388-91. doi: 10.1097/SLA.0b013e31819a47d2.
Abstract/Text OBJECTIVE: To compare the clinical outcome of patients with subclinical Cushing syndrome (SCS) due to an adrenal incidentaloma (the autonomous hypersecretion of a small amount of cortisol, which is not enough to cause clinically-evident disease) who underwent surgery or were managed conservatively.
SUMMARY BACKGROUND DATA: The most appropriate management of SCS patients is controversial, either adrenalectomy or close follow-up being recommended for their treatment.
METHODS: Over a 15-year period, 45 SCS patients were randomly selected to undergo surgery (n = 23) or conservative management (n = 22). All surgical procedures were laparoscopic adrenalectomies performed by the same surgeon. All patients were followed up (mean, 7.7 years; range, 2-17 years) clinically by 2 experienced endocrinologists 6 and 12 months after surgery and then yearly, or yearly after joining the trial, particularly monitoring diabetes mellitus (DM), arterial hypertension, hyperlipidemia, obesity, and osteoporosis. The study end point was the clinical outcome of SCS patients who underwent adrenalectomy versus those managed conservatively.
RESULTS: All 23 patients in the surgical arm had elective surgery. Another 3 patients randomly assigned to conservative management crossed over to the surgical group due to an increasing adrenal mass >3.5 cm. In the surgical group, DM normalized or improved in 62.5% of patients (5 of 8), hypertension in 67% (12 of 18), hyperlipidemia in 37.5% (3 of 8), and obesity in 50% (3 of 6). No changes in bone parameters were seen after surgery in SCS patients with osteoporosis. On the other hand, some worsening of DM, hypertension, and hyperlipidemia was noted in conservatively-managed patients.
CONCLUSIONS: Based on the results of this study, laparoscopic adrenalectomy performed by skilled surgeons appears more beneficial than conservative management for SCS patients complying with our selection criteria. This trial is registered with Australian Clinical Trials Registry number, ANZCTR12608000567325.

PMID 19247023  Ann Surg. 2009 Mar;249(3):388-91. doi: 10.1097/SLA.0b01・・・
著者: Gaspar A Motta-Ramirez, Erick M Remer, Brian R Herts, Inderbir S Gill, Amir H Hamrahian
雑誌名: AJR Am J Roentgenol. 2005 Sep;185(3):684-8. doi: 10.2214/ajr.185.3.01850684.
Abstract/Text OBJECTIVE: The objective of our study was to determine the prevalence of incidental pheochromocytomas, whether their imaging characteristics differ from those of pheochromocytomas in symptomatic patients, and whether they differ from adenomas using CT densitometry.
MATERIALS AND METHODS: The records from 335 adrenalectomies performed at our institution from 1995 to 2002 were reviewed, and 71 pheochromocytomas were identified. Thirty-three patients had CT examinations performed at our institution that were available for retrospective review. From electronic and hard-copy medical records, patient age and sex, the indications for imaging, and biochemistry activity were recorded. Pheochromocytomas were classified as symptomatic or incidental on the basis of clinical presentation. These groups were compared for differences in patient age, adrenal mass volume and maximal diameter based on CT dimensions, attenuation on unenhanced CT, attenuation on enhanced CT during the portal phase, the presence of calcifications, low attenuation or cystic changes, biochemical activity, and hypertension. Statistical significance was assessed with the Student's t test or chi-square test, as appropriate.
RESULTS: Nineteen incidental (57.6%) and 14 symptomatic (42.4%) adrenal pheochromocytomas were in the study. There was a significant difference between the two groups as to whether hypertension was present (incidental, 10/19 [52.6%]; symptomatic, 14/14 [100%]; p = 0.0025). We found a trend toward calcification present in more symptomatic patients (incidental, 0/19 [0%]; symptomatic, 4/14 [28.6%]; p = 0.0670). No statistically significant difference was noted in the mean patient age (incidental, 51.7 years; symptomatic, 45.9 years), mean volume of the mass (incidental, 74.0 cm(3); symptomatic, 78.2 cm(3)), mean maximal diameter of the mass (incidental, 5.26 cm; symptomatic, 5.33 cm), mean attenuation on unenhanced CT (incidental, 36.6 H; symptomatic, 34.2 H), mean attenuation on enhanced CT (incidental, 93.7 H; symptomatic, 104.3 H), necrosis score or biochemical activity (incidental, 17/18 [94.4%]; symptomatic, 12/14 [85.7%]). No attenuation value of any pheochromocytoma was less than 10 H on unenhanced CT (median, 35 H; range, 17-59 H).
CONCLUSION: In our study population, 57.6% of the pheochromocytomas were incidental, more than in most reported series. A history of hypertension was more frequent in the symptomatic group (p = 0.0025), but no radiologic parameters that allow differentiation of incidental and symptomatic pheochromocytomas were found. None of the pheochromocytomas had attenuation values of less than 10 H on unenhanced CT scans.

PMID 16120918  AJR Am J Roentgenol. 2005 Sep;185(3):684-8. doi: 10.221・・・
著者: William F Young
雑誌名: Clin Endocrinol (Oxf). 2007 May;66(5):607-18. doi: 10.1111/j.1365-2265.2007.02775.x.
Abstract/Text Great strides have been made in our understanding of the pathophysiology of primary aldosteronism syndrome since Conn's description of the clinical presentation of a patient with an aldosterone-producing adenoma (APA) more than 50 years ago. It is now recognized that the APA is just one of the seven subtypes of primary aldosteronism. APA and bilateral idiopathic hyperaldosteronism (IHA) are the most common subtypes of primary aldosteronism. Although most clinicians had thought primary aldosteronism to be a rare form of hypertension for more than three decades, it is now recognized to be the most common form of secondary hypertension. Using the plasma aldosterone to plasma renin activity ratio as a case-finding test, followed by aldosterone suppression confirmatory testing, has resulted in much higher prevalence estimates of 5-13% of all patients with hypertension. In addition, there has been a new recognition of the aldosterone-specific cardiovascular morbidity and mortality associated with aldosterone excess. Although thought to be daunting and complex in the past, the diagnostic approach to primary aldosteronism is straightforward and can be considered in three phases: case-finding tests, confirmatory tests and subtype evaluation tests. Patients with hypertension and hypokalaemia (regardless of presumed cause), treatment-resistant hypertension (three antihypertensive drugs and poor control), severe hypertension (>or= 160 mmHg systolic or >or= 100 mmHg diastolic), hypertension and an incidental adrenal mass, onset of hypertension at a young age or patients being evaluated for other forms of secondary hypertension should undergo screening for primary aldosteronism. In patients with suspected primary aldosteronism, screening can be accomplished by measuring a morning (preferably between 0800 and 1000 h) ambulatory paired random plasma aldosterone concentration (PAC) and plasma renin activity (PRA). An increased PAC:PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstrating inappropriate aldosterone secretion. Aldosterone suppression testing can be performed with orally administered sodium chloride and measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of PAC. Unilateral adrenalectomy in patients with APA or unilateral adrenal hyperplasia results in normalization of hypokalaemia in all these patients; hypertension is improved in all and is cured in approximately 30-60% of them. In bilateral adrenal forms of primary aldosteronism, unilateral or bilateral adrenalectomy seldom corrects the hypertension and they should be treated medically with a mineralocorticoid receptor antagonist.

PMID 17492946  Clin Endocrinol (Oxf). 2007 May;66(5):607-18. doi: 10.1・・・
著者: Anna M Sawka, Roman Jaeschke, Ravinder J Singh, William F Young
雑誌名: J Clin Endocrinol Metab. 2003 Feb;88(2):553-8. doi: 10.1210/jc.2002-021251.
Abstract/Text We compared the diagnostic efficacy of fractionated plasma metanephrine measurements to measurements of 24-h urinary total metanephrines and catecholamines in outpatients tested for pheochromocytoma at Mayo Clinic Rochester from January 1, 1999, until November 27, 2000. Catecholaminesecreting tumors were histologically proven. The sensitivity of fractionated plasma metanephrines was 97% (30 of 31 patients), compared with a sensitivity of 90% (28 of 31) for urinary total metanephrines and catecholamines (P = 0.63). The specificity of fractionated plasma metanephrines was 85% (221 of 261), compared with 98% (257 of 261; P < 0.001) for urinary measurements. The likelihood ratios for positive tests were 6.3 (95% confidence interval, 4.7 to 8.5) for fractionated plasma metanephrines and 58.9 (95% confidence interval, 22.1 to 156.9) for urinary total metanephrines and catecholamines. An adrenal pheochromocytoma was missed by urinary testing in two patients with familial syndromes and one asymptomatic patient with an incidentally discovered adrenal mass. An extra-adrenal paraganglioma was missed by plasma testing in one patient. In conclusion, measurements of 24-h urinary total metanephrines and catecholamines yield fewer false-positive results, an attribute preferred for testing low-risk patients, but fractionated plasma metanephrine measurements may be preferred in high-risk patients with familial endocrine syndromes.

PMID 12574179  J Clin Endocrinol Metab. 2003 Feb;88(2):553-8. doi: 10.・・・
著者: C G Perry, A M Sawka, R Singh, L Thabane, J Bajnarek, W F Young
雑誌名: Clin Endocrinol (Oxf). 2007 May;66(5):703-8. doi: 10.1111/j.1365-2265.2007.02805.x. Epub 2007 Mar 27.
Abstract/Text BACKGROUND: There are limitations to currently available biochemical tests for pheochromocytoma. Our objective was to evaluate the diagnostic efficacy of a novel tandem mass spectrometry assay for the measurement of fractionated urinary metanephrines in patients suspected to have a pheochromocytoma. We also developed clinically based cut-offs for positivity of this measurement.
METHODS: We examined the medical records of 506 patients (including 102 patients with a catecholamine-producing tumour) who underwent measurement of 24-h urinary fractionated metanephrines using tandem mass spectrometry as well as adrenal imaging at Mayo Clinic, Rochester. The cut-offs for positivity were defined as follows: total metanephrines (sum of the metanephrine fractions) 5163 nmol/day, normetanephrine fraction 4001 nmol/day, metanephrine fraction 1531 nmol/day. Receiver operating characteristic (ROC) curves were constructed.
RESULTS: The diagnostic efficacy was as follows: normetanephrine fraction sensitivity 87.3% [(95% confidence interval (CI) 79.4-92.4%], specificity 95.0% (92.5-96.8); metanephrine fraction sensitivity 56.9% (47.2-66.1), specificity 95.0% (92.5-96.8); elevation of either normetanephrine or metanephrine fraction sensitivity 97.1% (91.7-99.0) and specificity 91.1% (87.9-93.5). Areas under the ROC curves (AUCs) were 0.972 (95% CI 0.955-0.990) for the normetanephrine fraction, 0.800 (0.741-0.858) for the metanephrine fraction, 0.991 (0.985-0.996) for total metanephrines, and 0.991 (0.985-0.996) for a regression-derived ROC curve incorporating both the metanephrine and normetanephrine fractions.
CONCLUSION: Measurement of 24-h urinary fractionated metanephrines by a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of pheochromocytoma.

PMID 17388796  Clin Endocrinol (Oxf). 2007 May;66(5):703-8. doi: 10.11・・・
著者: Cristina Eller-Vainicher, Valentina Morelli, Antonio Stefano Salcuni, Massimo Torlontano, Francesca Coletti, Laura Iorio, Antonello Cuttitta, Angelo Ambrosio, Leonardo Vicentini, Vincenzo Carnevale, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani, Iacopo Chiodini
雑誌名: Eur J Endocrinol. 2010 Jan;162(1):91-9. doi: 10.1530/EJE-09-0775. Epub 2009 Oct 1.
Abstract/Text OBJECTIVE: Few data are available regarding the need of steroid substitutive therapy after unilateral adrenalectomy for adrenal incidentaloma (AI). It is unknown whether, before surgery, the hypothalamic-pituitary-adrenal (HPA) axis secretion parameters can predict post-surgical hypocortisolism.
AIM: This study aimed to evaluate whether, in AI patients undergoing unilateral adrenalectomy, post-surgical hypocortisolism could be predicted by the parameters of HPA axis function.
DESIGN: Prospective, multicenter.
METHODS: A total of 60 patients underwent surgical removal of AI (surgical indication: 29 subclinical hypercortisolism (SH); 31 AI dimension). Before surgery, SH was diagnosed in patients presenting at least three criteria out of urinary free cortisol (UFC) levels>60 microg/24 h, cortisol after 1-mg dexamethasone suppression test (1 mg-DST)>3.0 microg/dl, ACTH levels<10 pg/ml, midnight serum cortisol (MSC)>5.4 microg/dl. Two months after surgery, HPA axis function was assessed by low dose ACTH stimulation test or insulin tolerance test when needed: 39 patients were affected (Group B) and 21 were not affected (Group A) with hypocortisolism. The accuracy in predicting hypocortisolism of pre-surgical HPA axis parameters or their combinations was evaluated.
RESULTS: The presence of >2 alterations among 1 mg-DST>5.0 microg/dl, ACTH<10 pg/ml, elevated UFC and MSC has the highest odds ratio (OR) for predicting post-surgical hypocortisolism (OR 10.45, 95% confidence interval, CI 2.54-42.95, P=0.001). Post-surgical hypocortisolism was predicted with 100% probability by elevated UFC plus MSC levels, but not ruled out even in the presence of the normality of all HPA axis parameters.
CONCLUSION: Post-surgical hypocortisolism cannot be pre-surgically ruled out. A steroid substitutive therapy is indicated after unilateral adrenalectomy for SH or size of the adenoma.

PMID 19797503  Eur J Endocrinol. 2010 Jan;162(1):91-9. doi: 10.1530/EJ・・・
著者: A Angeli, G Osella, A Alì, M Terzolo
雑誌名: Horm Res. 1997;47(4-6):279-83.
Abstract/Text BACKGROUND: The incidental discovery of an adrenal mass raises the problem of distinguishing the frequent benign masses from the infrequent malignant ones that require surgery. At present, univocal guidelines to approach this problem are not available. The aim of the present study was to perform a multicentric retrospective analysis of adrenal masses incidentally discovered (adrenal incidentalomas).
PATIENTS AND METHODS: Hospital records of adrenal incidentalomas diagnosed over a 15-year period in 29 surgical and medical centers in Italy were scrutinized. Collected cases were 1,013, and 887 were analyzed.
RESULTS: The majority of patients were in the 5th and 6th decade and females were predominantly affected. The frequency of adrenocortical cancer was 12% among operated patients (316 cases). The tumor diameter was highly correlated with the risk of malignancy, as well as the CT characteristics such as density, shape and margins. The frequency of pheochromocytoma was 10% among operated patients.
CONCLUSIONS: The occurrence of incidentally discovered adrenocortical carcinomas and pheochromocytomas is not rare. Evaluation of the mass size and CT characteristics are simple and effective methods to differentiate malignant lesions. Biochemical screening for pheochromocytoma is mandatory before surgery.

PMID 9167965  Horm Res. 1997;47(4-6):279-83.
著者: Jacqueline Dinnes, Irina Bancos, Lavinia Ferrante di Ruffano, Vasileios Chortis, Clare Davenport, Susan Bayliss, Anju Sahdev, Peter Guest, Martin Fassnacht, Jonathan J Deeks, Wiebke Arlt
雑誌名: Eur J Endocrinol. 2016 Aug;175(2):R51-64. doi: 10.1530/EJE-16-0461. Epub 2016 Jun 2.
Abstract/Text OBJECTIVE: Adrenal masses are incidentally discovered in 5% of CT scans. In 2013/2014, 81 million CT examinations were undertaken in the USA and 5 million in the UK. However, uncertainty remains around the optimal imaging approach for diagnosing malignancy. We aimed to review the evidence on the accuracy of imaging tests for differentiating malignant from benign adrenal masses.
DESIGN: A systematic review and meta-analysis was conducted.
METHODS: We searched MEDLINE, EMBASE, Cochrane CENTRAL Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index, and ZETOC (January 1990 to August 2015). We included studies evaluating the accuracy of CT, MRI, or (18)F-fluoro-deoxyglucose (FDG)-PET compared with an adequate histological or imaging-based follow-up reference standard.
RESULTS: We identified 37 studies suitable for inclusion, after screening 5469 references and 525 full-text articles. Studies evaluated the accuracy of CT (n=16), MRI (n=15), and FDG-PET (n=9) and were generally small and at high or unclear risk of bias. Only 19 studies were eligible for meta-analysis. Limited data suggest that CT density >10HU has high sensitivity for detection of adrenal malignancy in participants with no prior indication for adrenal imaging, that is, masses with ≤10HU are unlikely to be malignant. All other estimates of test performance are based on too small numbers.
CONCLUSIONS: Despite their widespread use in routine assessment, there is insufficient evidence for the diagnostic value of individual imaging tests in distinguishing benign from malignant adrenal masses. Future research is urgently needed and should include prospective test validation studies for imaging and novel diagnostic approaches alongside detailed health economics analysis.

© 2016 The authors.
PMID 27257145  Eur J Endocrinol. 2016 Aug;175(2):R51-64. doi: 10.1530/・・・
著者: Electron Kebebew
雑誌名: N Engl J Med. 2021 Apr 22;384(16):1542-1551. doi: 10.1056/NEJMcp2031112.
Abstract/Text
PMID 33882207  N Engl J Med. 2021 Apr 22;384(16):1542-1551. doi: 10.10・・・
著者: Melvin M Grumbach, Beverly M K Biller, Glenn D Braunstein, Karen K Campbell, J Aidan Carney, Paul A Godley, Emily L Harris, Joseph K T Lee, Yolanda C Oertel, Mitchell C Posner, Janet A Schlechte, H Samuel Wieand
雑誌名: Ann Intern Med. 2003 Mar 4;138(5):424-9.
Abstract/Text The National Institutes of Health Consensus Development Program convened surgeons, endocrinologists, pathologists, biostatisticians, radiologists, oncologists, and other health care professionals, as well as members of the general public, to address the causes, prevalence, and natural history of clinically inapparent adrenal masses, or "incidentalomas"; the appropriate evaluation and treatment of such masses; and directions for future research. Improvements in abdominal imaging techniques have increased detection of adrenal incidentalomas, and because the prevalence of these masses increases with age, appropriate management of adrenal tumors will be a growing challenge in our aging society. To address six predetermined questions, the 12-member nonfederal, nonadvocate state-of-the-science panel heard presentations from 21 experts in adrenal incidentalomas and consulted a systematic review of medical literature on the topic provided by the Agency for Healthcare Research and Quality and an extensive bibliography developed by the National Library of Medicine. The panel recommended a 1-mg dexamethasone suppression test and measurement of plasma-free metanephrines for all patients with an adrenal incidentaloma; additional measurement of serum potassium and plasma aldosterone concentration-plasma renin activity ratio for patients with hypertension; and surgery for patients with biochemical evidence of pheochromocytoma, patients with tumors greater than 6 cm, and patients with tumors greater than 4 cm who also meet other criteria. The panel also advocated a multidisciplinary approach to managing adrenal incidentalomas. The statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the federal government.

PMID 12614096  Ann Intern Med. 2003 Mar 4;138(5):424-9.
著者: Dieter H Szolar, Melvyn Korobkin, Pia Reittner, Andrea Berghold, Thomas Bauernhofer, Harald Trummer, Helmut Schoellnast, Klaus W Preidler, Hellmuth Samonigg
雑誌名: Radiology. 2005 Feb;234(2):479-85. doi: 10.1148/radiol.2342031876.
Abstract/Text PURPOSE: To retrospectively measure the adrenal gland attenuation and the percentage loss of adrenal gland enhancement at delayed contrast medium-enhanced computed tomography (CT) in patients with adrenocortical carcinomas and pheochromocytomas and to compare these data with those in patients with adenomas and metastases.
MATERIALS AND METHODS: The study protocol was approved by the ethics committee, which waived informed consent. Eleven patients with proved adrenocortical carcinoma, 17 with proved pheochromocytoma, 23 with adrenal adenoma, and 16 with metastasis to the adrenal gland underwent helical CT. Nonenhanced CT was followed by contrast-enhanced CT 1 minute and 10 minutes later. Attenuation and enhancement loss values were calculated.
RESULTS: The mean attenuation of adenomas (8 HU +/- 18 [standard deviation]) was significantly lower than those of adrenocortical carcinomas (39 HU +/- 14), pheochromocytomas (44 HU +/- 11), and metastases (34 HU +/- 11) on nonenhanced CT scans (P < .001). Although the mean attenuation values for nonadenomas (ie, adrenocortical carcinomas, pheochromocytomas, and metastases) were significantly higher than the value for adenomas on the 1-minute contrast-enhanced CT scans (P < .001), there was more overlap in attenuation between adenomas and nonadenomas on contrast-enhanced scans than on nonenhanced scans. On the 10-minute delayed contrast-enhanced scans, the mean attenuation of adenomas (32 HU +/- 17) was significantly lower than the mean attenuations of carcinomas (72 HU +/- 15), pheochromocytomas (83 HU +/- 14), and metastases (66 HU +/- 13) (P < .001). At optimal threshold values of 50% for absolute percentage of enhancement loss and 40% for relative percentage of enhancement loss at 10 minutes, both the sensitivity and the specificity for the diagnosis of adenoma were 100% when adenomas were compared with carcinomas, pheochromocytomas, and metastases.
CONCLUSION: The enhancement loss in adrenocortical carcinomas and pheochromocytomas is similar to that in adrenal metastases but significantly less than that in adrenal adenomas. The percentage change in contrast material washout is a useful adjunct to absolute CT attenuation values in differentiating adrenal adenomas from adrenocortical carcinomas and pheochromocytomas.

(c) RSNA, 2005.
PMID 15671003  Radiology. 2005 Feb;234(2):479-85. doi: 10.1148/radiol.・・・
著者: C S Peña, G W Boland, P F Hahn, M J Lee, P R Mueller
雑誌名: Radiology. 2000 Dec;217(3):798-802. doi: 10.1148/radiology.217.3.r00dc29798.
Abstract/Text PURPOSE: To determine whether computed tomographic (CT) scans and attenuation measurements on contrast material-enhanced and nonenhanced CT scans could be used to characterize adrenal masses, in particular, to characterize these lesions by using adrenal washout characteristics at contrast-enhanced CT.
MATERIALS AND METHODS: Eighty-six patients (49 men, 37 women; age range, 29-86 years; mean age, 72 years) with 101 adrenal lesions depicted at contrast-enhanced CT underwent delayed (mean, 9 minutes) enhanced scanning. Seventy-eight patients also underwent nonenhanced CT. Mean diameter of the benign lesions was 2.1 cm (range, 1.0-4.2 cm); mean diameter of the malignant lesions was 2.3 cm (range, 1.0-4.1 cm). Region-of-interest measurements were obtained at nonenhanced, dynamic enhanced, and delayed enhanced CT and were used to calculate a relative percentage washout as follows: 1 - (Hounsfield unit measurement on delayed image / Hounsfield unit measurement on dynamic image) x 100%.
RESULTS: Ninety-nine of 101 lesions were correctly characterized as benign or malignant with a relative percentage washout threshold of 50% on delayed scans; benign lesions demonstrated more than 50% washout; and malignant lesions, less than 50% washout. Two benign lesions demonstrating less than 50% washout were characterized as benign by using conventional CT.
CONCLUSION: Calculation of relative percentage washout on dynamic and delayed enhanced CT scans may lead to a highly specific test for adrenal lesion characterization, reduce the need for, and possibly obviate, follow-up imaging or biopsy.

PMID 11110946  Radiology. 2000 Dec;217(3):798-802. doi: 10.1148/radiol・・・
著者: M Korobkin, F J Brodeur, I R Francis, L E Quint, N R Dunnick, F Londy
雑誌名: AJR Am J Roentgenol. 1998 Mar;170(3):747-52. doi: 10.2214/ajr.170.3.9490968.
Abstract/Text OBJECTIVE: The purpose of this study was to analyze the CT contrast enhancement washout curves of adrenal masses and to determine the earliest time after initial enhancement that differentiation of adenomas from nonadenomas is possible.
MATERIALS AND METHODS: Contrast enhancement washout curves were generated after delayed contrast-enhanced CT scans of 52 adrenal adenomas and 24 nonadenomas. The optimal threshold value and corresponding sensitivity and specificity for the diagnosis of adenoma were determined according to attenuation values. Also, we calculated the percentage and relative percentage of enhancement washout at time delays from 5 to 45 min after initial enhancement.
RESULTS: The mean percentage of enhancement washout for adrenal adenomas was 51% at 5 min and 70% at 15 min, compared with 8% and 20%, respectively, for nonadenomas. The sensitivity and specificity for the diagnosis of adenoma were both 96% at a threshold attenuation value of 37 H on the 15-min delayed enhanced scan.
CONCLUSION: On CT, adrenal adenomas show a much earlier and more rapid washout of contrast enhancement than do nonadenomas. Adenomas and nonadenomas can be differentiated by attenuation values or the percentage or relative percentage of washout as early as 5-15 min after enhancement.

PMID 9490968  AJR Am J Roentgenol. 1998 Mar;170(3):747-52. doi: 10.22・・・
著者: J T Lenert, C C Barnett, A P Kudelka, R V Sellin, R F Gagel, V G Prieto, J M Skibber, M I Ross, P W Pisters, S A Curley, D B Evans, J E Lee
雑誌名: Surgery. 2001 Dec;130(6):1060-7. doi: 10.1067/msy.2001.118369.
Abstract/Text BACKGROUND: Adrenal abnormalities are often identified on imaging studies performed during the staging of patients presenting with a new malignancy or restaging of patients with a history of a malignancy.
METHODS: We reviewed the records of patients who underwent surgical resection of an adrenal mass identified in the setting of previously or newly diagnosed extra-adrenal malignancy.
RESULTS: Eighty-one patients with an adrenal mass and recently diagnosed malignancy (n = 24) or history of a malignancy (n = 57) underwent adrenalectomy. In 42 patients (52%) the adrenal mass was a metastasis. In 39 patients (48%) the adrenal mass was an additional primary adrenal tumor process: 19 pheochromocytomas, (14 syndrome-associated, 5 sporadic), 13 cortical adenomas, 3 adrenocortical carcinomas, 2 ganglioneuromas, and 2 cases of nodular hyperplasia.
CONCLUSIONS: In this series nearly half of the patients with cancer and an adrenal mass had adrenal pathologic condition independent of their primary malignancy. Despite the presence of a newly diagnosed malignancy or history of malignancy, all patients with an adrenal mass should undergo a standard hormone evaluation to confirm that the mass is not a functional neoplasm. An assumption that the adrenal mass is metastatic disease will be wrong in up to 50% of such patients.

PMID 11742339  Surgery. 2001 Dec;130(6):1060-7. doi: 10.1067/msy.2001.・・・
著者: Kenneth R Hess, Gauri R Varadhachary, Sarah H Taylor, Wei Wei, Martin N Raber, Renato Lenzi, James L Abbruzzese
雑誌名: Cancer. 2006 Apr 1;106(7):1624-33. doi: 10.1002/cncr.21778.
Abstract/Text BACKGROUND: Unique metastatic patterns cited in the literature often arise from anecdotal clinical observations and autopsy reports. The authors analyzed clinical data from a large number of patients with histologically confirmed, distant-stage adenocarcinoma to evaluate metastatic patterns.
METHODS: Tumor registry data were collected between 1994-1996 on 11 primary tumor sites and 15 metastatic sites from 4399 patients. The primary and metastatic sites were cross-tabulated in various ways to identify patterns, and the authors developed algorithms by using multinomial logistic regression analysis to predict the locations of primary tumors based on metastatic patterns.
RESULTS: Three primary tumors had single, dominant metastatic sites: ovary to abdominal cavity (91%), prostate to bone (90%), and pancreas to liver (85%). The liver was the dominant metastatic site for gastrointestinal (GI) primary tumors (71% of patients), whereas bone and lung metastases were noted most frequently in non-GI primary tumors (43% and 29%, respectively). In a study of combinations of liver, abdominal cavity, and bone metastases, 86% of prostate primary tumors had only bone metastases, 80% of ovarian primary tumors had only abdominal cavity metastases, and 74% of pancreas primary tumors had only liver metastases. A single organ was the dominant source of metastases in 7 sites: axillary lymph node from the breast (97%), intestinal lymph node from the colon (84%), thoracic lymph node from the lung (66%), brain from the lung (64%), mediastinal lymph node from the lung (62%), supraclavicular lymph node from the breast (51%), and adrenal gland from the lung (51%).
CONCLUSIONS: The algorithms that the authors developed achieved a cross-validated accuracy of 64% and an accuracy of 64% on an 1851-patient independent test set, compared with 9% accuracy when a random classifier was used.

Copyright 2006 American Cancer Society.
PMID 16518827  Cancer. 2006 Apr 1;106(7):1624-33. doi: 10.1002/cncr.21・・・
著者: J E Lee, D B Evans, R C Hickey, S I Sherman, R F Gagel, M C Abbruzzese, J L Abbruzzese
雑誌名: Surgery. 1998 Dec;124(6):1115-22.
Abstract/Text BACKGROUND: Fine-needle aspiration biopsy to identify adrenal metastasis from an occult primary malignancy has been recommended as part of the evaluation of the patient who presents with an incidentally discovered adrenal mass. This recommendation was assessed by examining the frequency of adrenal involvement in patients with suspected unknown primary cancer.
METHODS: Data from 1715 patients referred for evaluation of suspected unknown primary cancer were retrospectively reviewed.
RESULTS: Of 1639 patients found to have cancer, the adrenal gland was identified as a site of involvement at presentation in 95 (5.8%). Involvement was limited to the adrenal gland in 4 patients (0.2%). All 4 patients had large (> or = 6 cm) adrenal tumors, 3 of 4 had bilateral involvement, and all had symptoms that otherwise mandated evaluation for an occult malignancy; none had a true adrenal incidentaloma.
CONCLUSIONS: Although cancer of an unknown primary site occasionally involves the adrenal gland, metastatic cancer presenting as a true adrenal incidentaloma is extremely rare. Therefore, in the absence of a history of prior malignancy or symptoms, physical examination findings, radiographic findings, or laboratory findings suggestive of an occult malignancy, we do not recommend fine-needle aspiration biopsy as part of the diagnostic evaluation of the patient who presents with a unilateral adrenal mass.

PMID 9854592  Surgery. 1998 Dec;124(6):1115-22.
著者: M G Harisinghani, M M Maher, P F Hahn, D A Gervais, K Jhaveri, J Varghese, P R Mueller
雑誌名: Clin Radiol. 2002 Oct;57(10):898-901.
Abstract/Text PURPOSE: Percutaneous CT guided biopsy is accepted as a safe procedure for the diagnosis of indeterminate adrenal masses in oncologic patients. The purpose of this study was to evaluate the accuracy of a 'negative for tumour' adrenal biopsy in the oncologic patient population by assessing subsequent outcome including clinical course, size and imaging characteristics of the adrenal lesions on follow-up imaging studies and pathological findings at re-biopsy or following adrenal mass resection.
MATERIALS AND METHODS: Retrospective analysis of 225 oncological patients (FM, 128;87; age range 33-87 years, mean age 66 years) who had undergone CT guided biopsies of an adrenal mass over a 5-year period was performed. Those patients with a report consistent with 'negative for malignancy' were evaluated by reviewing the medical records for patient demographics, primary malignancy, histology of adrenal tumour, subsequent surgical interventions, repeat adrenal biopsy under image guidance, by open surgery or at autopsy, subsequent abdominal imaging in which the adrenal gland was imaged, and long-term outcome including hospital admissions, or death.
RESULTS: Of the 225 CT-guided adrenal biopsies performed, 41 (18%) were negative for neoplasm. The primary neoplasm in these 41 patients included lung cancer (n=32), breast (n=5), renal cell carcinoma (n=2), bladder (n=1), and prostate (n=1). The size of the adrenal lesions ranged from 2.8-5 cm. Of the 41 biopsies, which were negative for tumour; 10 were identified as adenomas and the rest showed benign adrenal cortical cells or hyperplasia on cytopathology and histopathology. Repeat biopsies were obtained in 13/41 (31%) patients; whereas 2/41 (5%) had their adrenal gland analyzed on post mortem examination. None of these 15 repeat evaluations yielded tumour.
CONCLUSION: In oncological patients, pathological analysis of tissue samples obtained by CT-guided percutaneous biopsy, suggesting benign aetiology, is reliable and predicts a benign course on long-term follow-up. A negative or benign pathology result for a CT guided percutaneous adrenal biopsy can be regarded as a true negative evaluation in oncological patients with no necessity to repeat the biopsy.

PMID 12413913  Clin Radiol. 2002 Oct;57(10):898-901.
著者: Ronald S Arellano, Mukesh G Harisinghani, Debra A Gervais, Peter F Hahn, Peter R Mueller
雑誌名: Curr Probl Diagn Radiol. 2003 Jan-Feb;32(1):3-10. doi: 10.1067/cdr.2003.120002.
Abstract/Text
PMID 12574782  Curr Probl Diagn Radiol. 2003 Jan-Feb;32(1):3-10. doi: ・・・
著者: T J Welch, P F Sheedy, D H Stephens, C M Johnson, S J Swensen
雑誌名: Radiology. 1994 Nov;193(2):341-4. doi: 10.1148/radiology.193.2.7972740.
Abstract/Text PURPOSE: To evaluate the indications for and complications, accuracy, and techniques of percutaneous adrenal biopsy performed from 1982 through 1991 at the authors' institution.
MATERIALS AND METHODS: Two hundred seventy-seven percutaneous adrenal biopsies were performed in 270 patients (175 male and 102 female patients, aged 31-84 years). Imaging studies and histories were reviewed, and each patient's case was followed up for at least 1 year after the biopsy. A patient was excluded from the study only if follow-up data could not be obtained.
RESULTS: The accuracy of percutaneous adrenal biopsy was 90% (249 of 277 biopsies). In the first 5 years of the study, the accuracy was 85% (87 of 102 biopsies); in the latter 5 years it was 93% (163 of 175 biopsies). The sensitivity was 81%, and the specificity was 99%. The positive predictive value was 99%, and the negative predictive value was 80%. The complication rate was 2.8%.
CONCLUSION: Percutaneous biopsy is a safe, accurate procedure for the diagnosis of pathologic conditions of the adrenal glands. The most common indication for a biopsy is the presence of an adrenal mass in a patient with lung cancer.

PMID 7972740  Radiology. 1994 Nov;193(2):341-4. doi: 10.1148/radiolog・・・
著者: G Casola, V Nicolet, E vanSonnenberg, C Withers, M Bretagnolle, R M Saba, P M Bret
雑誌名: Radiology. 1986 Jun;159(3):733-5. doi: 10.1148/radiology.159.3.3517958.
Abstract/Text Four unsuspected pheochromocytomas were discovered during percutaneous fine-needle biopsy of the adrenal gland under ultrasound (n = 1) and computed tomographic (n = 3) guidance. One patient suffered an acute episode of alternating hypertension and hypotension during the procedure. A second patient had no alterations in vital signs during the procedure but had a severe hypertensive crisis during induction of anesthesia at surgery. Neither biopsy nor surgery affected the vital signs in the other two patients. During biopsy study of adrenal lesions, the possibility of unsuspected pheochromocytoma should be considered, and the interventional radiologist must be familiar with the emergency treatment of hypotensive or hypertensive crises that may occur.

PMID 3517958  Radiology. 1986 Jun;159(3):733-5. doi: 10.1148/radiolog・・・
著者: S J McCorkell, N L Niles
雑誌名: AJR Am J Roentgenol. 1985 Jul;145(1):113-4. doi: 10.2214/ajr.145.1.113.
Abstract/Text
PMID 3873829  AJR Am J Roentgenol. 1985 Jul;145(1):113-4. doi: 10.221・・・
著者: William F Young
雑誌名: N Engl J Med. 2007 Feb 8;356(6):601-10. doi: 10.1056/NEJMcp065470.
Abstract/Text
PMID 17287480  N Engl J Med. 2007 Feb 8;356(6):601-10. doi: 10.1056/NE・・・
著者: Georg Mansmann, Joseph Lau, Ethan Balk, Michael Rothberg, Yukitaka Miyachi, Stefan R Bornstein
雑誌名: Endocr Rev. 2004 Apr;25(2):309-40. doi: 10.1210/er.2002-0031.
Abstract/Text Clinically inapparent adrenal masses are incidentally detected after imaging studies conducted for reasons other than the evaluation of the adrenal glands. They have frequently been referred to as adrenal incidentalomas. In preparation for a National Institutes of Health State-of-the-Science Conference on this topic, extensive literature research, including Medline, BIOSIS, and Embase between 1966 and July 2002, as well as references of published metaanalyses and selected review articles identified more than 5400 citations. Based on 699 articles that were retrieved for further examination, we provide a comprehensive update of the diagnostic and therapeutic approaches focusing on endocrine and radiological features as well as surgical options. In addition, we present recent developments in the discovery of tumor markers, endocrine testing for subclinical disease including autonomous glucocorticoid hypersecretion and silent pheochromocytoma, novel imaging techniques, and minimally invasive surgery. Based on the statements of the conference, the available literature, and ongoing studies, our aim is to provide practical recommendations for the management of this common entity and to highlight areas for future studies and research.

PMID 15082524  Endocr Rev. 2004 Apr;25(2):309-40. doi: 10.1210/er.2002・・・
著者: Laurent Brunaud, Electron Kebebew, Frederic Sebag, Rasa Zarnegar, Orlo H Clark, Quan-Yang Duh
雑誌名: Med Sci Monit. 2006 Sep;12(9):CR355-62.
Abstract/Text BACKGROUND: The optimal strategy remains controversial for adrenal incidentaloma, 4 to 6 cm in size, nonfunctioning, and without malignant imaging characteristics. A decision analysis model was used to identify relevant variables for selecting the optimal management (observation versus adrenalectomy).
MATERIAL/METHODS: Risk/benefit analysis in tertiary care center. The probabilities of each health outcome states were determined by a review of the literature from 1980 to 2002 (n=2844 patients); and from a retrospective review of experience at University of California San Francisco (UCSF).
RESULTS: The baseline probabilities of morbidity after laparoscopic unilateral adrenalectomy and a new indication developing during initial observation (hypersecretion, size increase, malignancy) were 7.8% and 3.1%, respectively. We found observation to be the preferred approach when using baseline probabilities and utilities. Laparoscopic adrenalectomy becomes the preferred approach however if: (1) The morbidity rate from laparoscopic unilateral adrenalectomy is < 3.0%, 2) The probability of a new indication developing for adrenalectomy during observation is > 7.5%, 3) A patient's perspective of observation has a utility of lower than 98.6%, and (4) A patient views having a complication from adrenalectomy is not much deleterious (utility > 88.1%).
CONCLUSIONS: This decision analysis model identifies the important variables for selecting the optimal management approach for adrenal incidentalomas. These results can be used to select the optimal management strategy based on individual patient preference and surgeon-specific complication rate.

PMID 16940927  Med Sci Monit. 2006 Sep;12(9):CR355-62.
著者: Yogish C Kudva, Anna M Sawka, William F Young
雑誌名: J Clin Endocrinol Metab. 2003 Oct;88(10):4533-9. doi: 10.1210/jc.2003-030720.
Abstract/Text
PMID 14557417  J Clin Endocrinol Metab. 2003 Oct;88(10):4533-9. doi: 1・・・

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