今日の臨床サポート

成人成長ホルモン分泌不全症

著者: 福田いずみ 日本医科大学大学院医学研究科 内分泌糖尿病代謝内科学分野

監修: 平田結喜緒 公益財団法人 兵庫県予防医学協会 健康ライフプラザ

著者校正/監修レビュー済:2021/01/28
参考ガイドライン:
  1. 日本内分泌学会成人成長ホルモン分泌不全症の診断と治療の手引き(厚生労働科学研究費補助金難治性疾患等政策研究事業 間脳下垂体機能障害に関する調査研究班 平成30年度改訂、日本内分泌学会雑誌95 Suppl, p36-39, 2019)
  1. The Endocrine Society(米国内分泌学会):Evaluation and Treatment of Adult Growth Hormone Deficiency:An Endocrine Society Clinical Practice Guideline(文献J Clin Endocrinol Metab 96: 1587–1609, 2011)
患者向け説明資料

概要・推奨   

  1. 小児期にGH分泌不全性低身長症と診断されGH投与歴がある症例が、すべて成人GH分泌不全症に移行するとは限らない。また、成人期に新規に特発性単独GH分泌不全症が発症する可能性は、現在のところ低いと考えられている(推奨度1)
  1. 小児がん経験者、頭部外傷やクモ膜下出血の既往がGH分泌不全症の原因となることもある。頭部外傷やクモ膜下出血の既往がある場合は、発症後12カ月以降に必要に応じて下垂体機能の評価を行う(推奨度2)。
  1. GH投与は少量(3 μg/kg体重/日)より開始し、臨床症状、血中IGF-I値などの状況に応じて漸増する。その際、GHの吸収量やGHに対する感受性には個人差があり、GHの維持量については体重のみを考慮した一律の設定ではなく、個別の調節を行う方がよいとの意見もある(推奨度1)特に高齢者では少量からの投与開始が望ましい。
  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
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
福田いずみ : 特に申告事項無し[2021年]
監修:平田結喜緒 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 平成30年度にわが国の診断と治療の手引きが更新された。これをもとに一部改訂を行った。本症の診断に際して大きな変更点はないが、原因となる病態に抗PIT-1抗体症候群や小児がん経験者などの基礎疾患が新たに追加されている。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 成長ホルモン(GH)分泌不全症とは、成長ホルモンの分泌不全により、易疲労感、スタミナや集中力の低下などの自覚症状、皮膚の乾燥と菲薄化、体脂肪(内臓脂肪)の増加と除脂肪体重の低下、骨量や筋力低下などの所見が認められるようになる疾患である。
  1. 成人の成長ホルモン(GH)分泌不全症の診断に際しては、視床下部―下垂体領域の器質性病変がある場合、または、その既往や治療歴を有する症例を対象としてスクリーニングを行う。
  1. 小児期発症例(成長ホルモン分泌不全性低身長)では成長障害を伴うが、性腺機能低下症を合併しているケースや適切なGH補充療法を受けた症例では、必ずしも成人期に成長障害がみられるわけではない。
  1. 本症の診断にはGH分泌刺激試験を行い、その際のGH頂値より判定する。血中IGF-Ⅰ値は年齢・性別基準値に比べ低値であることが多いが基準値内であっても本症を否定することはできない[1]
  1. 本症では、GHを含めた複数の下垂体ホルモンの分泌低下(下垂体機能低下症)を合併することが多い。
  1. 成長ホルモン分泌不全症(下垂体前葉機能低下症)は指定難病であり、「確実例」で認定基準を満たす場合には申請し認可されると、保険料の自己負担分の一部が公費負担として助成される。(平成27年1月施行)
  1. 難病法に基づく医療費助成制度
 
  1. 小児期にGH分泌不全性低身長症と診断されGH投与歴がある症例が、すべて成人GH分泌不全症に移行するとは限らない。また、成人期に新規に特発性単独GH分泌不全症が発症する可能性は、現在のところ低いと考えられている(推奨度1G)(参考文献:[2][3][4]
  1. 研究背景:小児期にGH分泌不全性低身長症と診断された症例に対して、成長促進を目的としたGH治療の終了後にGH治療をいったん中止後、GH分泌刺激試験を施行して、成人期におけるGH分泌能を再度評価した報告がある。
  1. 研究事例:小児期にGH分泌不全性低身長症と診断されGH治療を受けた131症例のうち、特発性と診断されていた症例では、成長終了後の再評価時に成人GH分泌不全症の診断基準を満たしていた症例は38%であった。一方、器質性と診断されていた症例では、その90%が成人期にもGH分泌不全症の基準を満たしていた。
  1. 小児期発症のGH分泌不全症のうち、GHの合成過程や転写因子に関わる遺伝子変異(GH-1遺伝子変異、Pit-1遺伝子変異など)が原因である症例、3系統以上の下垂体ホルモン分泌不全症を有する症例では、成人期以降もGH分泌不全が存続すると考えられるが、そのほかの症例については、成長が終了した時点で1カ月間GHを休薬したうえで再度GH分泌刺激試験による評価を行い、成人GH分泌不全症の診断を満たすか、確認する必要がある。
  1. 結論:小児期にGH分泌不全性低身長症と診断された症例では、若年成人期にGH治療をいったん中止後、GH分泌刺激試験にてGH分泌能を再度評価する。特に、小児期にGH分泌不全の原因が特発性であったもの、GH単独欠損かGH以外に1系統の下垂体ホルモンの分泌低下のみを呈していた症例については、成人期にはもはや、成人GH分泌不全症の判定基準を満たさない症例がある。
 
  1. 頭部外傷やクモ膜下出血がGH分泌不全症の原因となることもある(推奨度2G)(参考文献:[5][6][3][4]
  1. 研究背景:頭部外傷やクモ膜下出血後の症例に対して負荷試験を施行し、下垂体機能を評価した報告が複数ある。
  1. 研究事例:Schneiderらのレビューによれば、頭部外傷後、クモ膜下出血後の下垂体機能低下症の発症頻度は各々27.5%、47%であった。頭部外傷の重症度と後遺症としての下垂体機能低下症の発症率は必ずしも相関しない。受傷後、一時的にGH系が傷害を受けてもその後に回復する症例もある。
  1. 結論:頭部外傷やクモ膜下出血の既往がある場合は、発症後12カ月以降に必要に応じて下垂体機能の評価を行う(推奨度2)。
  1. 追記:頭部外傷後のGH分泌不全症の発症頻度については、報告により6~33%と大きなばらつきがある。
 
  1. 成人期にはGH分泌不全症であっても血中IGF-Iが基準値内に保たれていることがあるため、血中IGF-Iが基準値内であることで成人GH分泌不全症の診断を除外することはできない(推奨度)(参考文献:[7][3][4]
  1. 研究背景:GH分泌刺激試験により成人GH分泌不全症と診断された症例における血中IGF-I値が調査されている。
  1. 研究事例:2003年に1,317例の成人GH分泌不全症を対象にGH補充前の血中IGF-I値を解析したところ、小児期発症の成人GH分泌不全症においてはIGF-I SDSが-2SDS以下と低値であった症例は86%であった。一方、成人期発症の成人GH分泌不全症では血中IGF-I値が低値を呈する症例は52%のみであった。
  1. 結論:成人期にはGH分泌不全症であっても血中IGF-Iが基準値内に保たれていることがあるため、血中IGF-Iが基準値内であることで、成人GH分泌不全症の診断を除外することはできない。一方、異化亢進状態や肝疾患などの素因がないのに血中IGF-Iが低下していることは、GH分泌不全症の診断のうえで参考になる所見である。
病歴・診察のポイント  
  1. 病歴では、視床下部―下垂体領域の器質性病変の合併ないし既往、またはその治療歴(手術および放射線治療)、小児期の癌治療、クモ膜下出血や重症頭部外傷などの既往の有無、周産期の異常(仮死など)の有無、下垂体機能低下症としてすでにホルモン補充療法を受けていないか、といった点について確認する。
  1. 問診所見では易疲労感、気力低下などの自覚症状の有無を確認する。

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文献 

著者: Tsuyoshi Isojima, Akira Shimatsu, Susumu Yokoya, Kazuo Chihara, Toshiaki Tanaka, Naomi Hizuka, Akira Teramoto, Ke-ita Tatsumi, Katsuhiko Tachibana, Noriyuki Katsumata, Reiko Horikawa
雑誌名: Endocr J. 2012 Sep 30;59(9):771-80. Epub 2012 May 19.
Abstract/Text Measurements of insulin-like growth factor-I (IGF-I) are useful not only for diagnosis and management of patients with growth hormone (GH)-related disorders but also for assessing nutritional status. We reported population-based references of serum IGF-I in 1996. However, they did not properly reflect data in the transition period from puberty to maturity. The aim of the present study was to re-establish a set of normative data for IGF-I for the Japanese population. The study included 1,685 healthy Japanese subjects (845 males, 840 females) from 0 to 83 years old. Subjects suffering from diseases that could affect IGF-I levels were excluded. Obese or extremely thin adult subjects were also excluded. IGF-I concentrations were determined by commercially available immunoradiometric assays. The reference intervals were calculated using the LMS method. Median IGF-I levels reached 310 ng/mL in males at the age of 14 years and 349 ng/mL in females at the age of 13 years, falling to 124 ng/mL and 103 ng/mL, respectively, by the age of 70 years. The mean pretreatment IGF-1 SD scores in patients with severe GH deficiency (GHD) obtained from the database of the Foundation for Growth Science and from clinical studies for adult GHD were -2.1±1.6 and -4.9±2.5, respectively. The present study established age- and gender-specific normative IGF-I data for the Japanese population and showed the utility of these references for screening patients with severe GHD.

PMID 22673406  Endocr J. 2012 Sep 30;59(9):771-80. Epub 2012 May 19.
著者: M Tauber, P Moulin, C Pienkowski, B Jouret, P Rochiccioli
雑誌名: J Clin Endocrinol Metab. 1997 Feb;82(2):352-6. doi: 10.1210/jcem.82.2.3726.
Abstract/Text GH state and auxological data after completion of GH therapy are reported in 131 patients (79 males, 52 females). They were treated from 1980-1994 for partial (n = 98) or complete (n = 33) GH deficiency (GHD), either idiopathic (n = 121) or organic (n = 10). A single stimulation test (clonidine+betaxolol) was used, and only 50 patients (38%) maintained a blunted response (GH peak below 10 micrograms/L). Although 9 of the 10 patients with organic GHD had an abnormal low GH peak, 67% of patients with idiopathic GHD normalized their GH secretion. This was particularly true of partial GHD patients (71% vs. 36% of complete GH-deficient patients). Based on a retest GH peak below 5 micrograms/L, only 23% of the patients were considered to be GH deficient and therefore candidates for GH treatment during adulthood. We found no significant difference between hormonal state at completion of treatment and initial GH deficiency, pubertal state, or sex, although we did find a significantly lower GH peak value before and after treatment in patients with elevated body mass index. Of the 14 obese children who were treated, 50% had an abnormally low serum insulin-like growth factor-I level, arguing for true GHD, and only two children remained obese at cessation of treatment. Auxological data showed that with a mean duration of treatment of 3.6 +/- 2.0 yr, patients classified as having complete GHD before treatment had significantly greater catch-up growth as expressed in SDS for height than patients with partial GHD (0.6 +/- 1.1 vs. 1.1 +/- 0.7 SDS, P < 0.05), and that boys grew better than girls (1.4 +/- 0.8 vs. 1.6 +/- 0.6 SDS) for height, P < 0.01). That catch-up growth was not correlated with the result of GH peak after cessation of treatment.

PMID 9024217  J Clin Endocrinol Metab. 1997 Feb;82(2):352-6. doi: 10.・・・
著者: Ken K Y Ho, 2007 GH Deficiency Consensus Workshop Participants
雑誌名: Eur J Endocrinol. 2007 Dec;157(6):695-700. doi: 10.1530/EJE-07-0631.
Abstract/Text OBJECTIVE: The GH Research Society held a Consensus Workshop in Sydney, Australia, 2007 to incorporate the important advances in the management of GH deficiency (GHD) in adults, which have taken place since the inaugural 1997 Consensus Workshop.
METHOD: Two commissioned review papers, previously published Consensus Statements of the Society and key questions were circulated before the Workshop, which comprised a rigorous structure of review with breakout discussion groups. A writing group transcribed the summary group reports for drafting in a plenary forum on the last day. All participants were sent a polished draft for additional comments and gave signed approval to the final revision.
CONCLUSION: Testing for GHD should be extended from hypothalamic-pituitary disease and cranial irradiation to include traumatic brain injury. Testing may indicate isolated GHD; however, idiopathic isolated GHD occurring de novo in the adult is not a recognized entity. The insulin tolerance test, combined administration of GHRH with arginine or growth hormone-releasing peptide, and glucagon are validated GH stimulation tests in the adult. A low IGF-I is a reliable diagnostic indicator of GHD in the presence of hypopituitarism, but a normal IGF-I does not rule out GHD. GH status should be reevaluated in the transition age for continued treatment to complete somatic development. Interaction of GH with other axes may influence thyroid, glucocorticoid, and sex hormone requirements. Response should be assessed clinically by monitoring biochemistry, body composition, and quality of life. There is no evidence that GH replacement increases the risk of tumor recurrence or de novo malignancy.

PMID 18057375  Eur J Endocrinol. 2007 Dec;157(6):695-700. doi: 10.1530・・・
著者: Mark E Molitch, David R Clemmons, Saul Malozowski, George R Merriam, Mary Lee Vance, Endocrine Society
雑誌名: J Clin Endocrinol Metab. 2011 Jun;96(6):1587-609. doi: 10.1210/jc.2011-0179.
Abstract/Text OBJECTIVE: The aim was to update The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency (GHD) previously published in 2006.
CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes.
CONCLUSIONS: GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks associated with GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.

PMID 21602453  J Clin Endocrinol Metab. 2011 Jun;96(6):1587-609. doi: ・・・
著者: Harald Jörn Schneider, Ilonka Kreitschmann-Andermahr, Ezio Ghigo, Günter Karl Stalla, Amar Agha
雑誌名: JAMA. 2007 Sep 26;298(12):1429-38. doi: 10.1001/jama.298.12.1429.
Abstract/Text CONTEXT: Neuroendocrine dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage may occur with a much higher prevalence than previously suspected. This sequela is a potentially serious but treatable complication of brain injury.
OBJECTIVE: To review research on hypothalamopituitary dysfunction as an underdiagnosed consequence of traumatic brain injury and subarachnoid hemorrhage, the natural history of this complication, and the potential clinical and public health implications of posttraumatic hypopituitarism.
EVIDENCE ACQUISITION: The MEDLINE database was searched for articles published between 2000 and 2007 using any combination of the terms traumatic brain injury or subarachnoid hemorrhage with pituitary, hypopituitarism, growth hormone deficiency, hypogonadism, hypocortisolism, hypothyroidism, or diabetes insipidus. The reference lists of articles identified by this search strategy were also searched. All articles reporting original data on endocrine outcomes after traumatic brain injury or aneurysmal subarachnoid hemorrhage in peer-reviewed journals with regard to prevalence, pathogenesis, risk factors, outcomes, and clinical course were selected. We pooled data and calculated prevalence rates and 95% confidence intervals (CIs).
RESULTS: We identified 19 studies including 1137 patients. The pooled prevalences of hypopituitarism in the chronic phase after traumatic brain injury and aneurysmal subarachnoid hemorrhage were 27.5% (95% confidence interval [CI], 22.8%-28.9%) and 47% (95% CI, 37.4%-56.8%), respectively. The pooled prevalence of hypopituitarism was greater in patients with severe compared with those with mild or moderate traumatic brain injury. Early neuroendocrine abnormalities were transient in some patients while, less commonly, hypopituitarism evolved over time in others. Patients with posttraumatic hypopituitarism showed an impaired quality of life and an adverse metabolic profile.
CONCLUSION: Hypopituitarism is a common complication of both traumatic brain injury and aneurysmal subarachnoid hemorrhage and might contribute to morbidity and poor recovery after brain injury.

PMID 17895459  JAMA. 2007 Sep 26;298(12):1429-38. doi: 10.1001/jama.29・・・
著者: E Ghigo, B Masel, G Aimaretti, J Léon-Carrión, F F Casanueva, M R Dominguez-Morales, E Elovic, K Perrone, G Stalla, C Thompson, R Urban
雑誌名: Brain Inj. 2005 Aug 20;19(9):711-24. doi: 10.1080/02699050400025315.
Abstract/Text PRIMARY OBJECTIVE: The goal of this consensus statement is to increase awareness among endocrinologists and physicians treating patients with traumatic brain injury (TBI) of the incidence and risks of hypopituitarism among patients with TBI.
RATIONALE: TBI poses significant risk to the pituitary gland, leading to elevated risks of diabetes, hypopituitarism and other endocrinopathies. Signs and symptoms associated with hypopituitarism often mimic the sequellae of TBI, although the severity of symptoms is not necessarily related to the severity of the injury. Patients with TBI-induced hypopituitarism may benefit both physically and psychologically from appropriate hormone replacement therapy (HRT). Participants at this unique consensus meeting attempted to define and spearhead an approach to increase awareness of the risks of TBI-induced endocrinopathies, in particular growth hormone deficiency (GHD), and to outline necessary and practical objectives for managing this condition.
RECOMMENDATIONS: Systematic screening of pituitary function is recommended for all patients with moderate-to-severe TBI at risk of developing pituitary deficits. Patients with hypopituitarism benefit from appropriate hormonal replacement and prospects for rehabilitation of patients with TBI-induced hypopituitarism may be enhanced by appropriate HRT. Further exploration of this possibility requires: (1) active collaboration between divisions of endocrinology and rehabilitation at the local level to perform a screening of pituitary function in patients after TBI, (2) creation of a consultancy service by endocrine societies for use by rehabilitation centres, (3) development of continuing medical education (CME) programmes that can be offered as crossover training to the physicians who manage the care of patients with TBIs, (4) targeting of patient organizations with educational information for dissemination to patients and their families, (5) continued efforts to more clearly define the population at greatest risk of TBI-induced hypopituitarism and (6) monitor results of efficacy studies as they become available to evaluate whether and how much replacement therapy can improve the symptoms of individuals with TBI-induced hypopituitarism.

PMID 16195185  Brain Inj. 2005 Aug 20;19(9):711-24. doi: 10.1080/02699・・・
著者: Catherine A Lissett, Peter Jönsson, John P Monson, Stephen M Shalet, KIMS International Board
雑誌名: Clin Endocrinol (Oxf). 2003 Dec;59(6):773-8. doi: 10.1046/j.1365-2265.2003.01884.x.
Abstract/Text BACKGROUND: IGF-I standard deviation score (SDS) is widely used in clinical practice; however, factors determining IGF-I SDS in GH-deficient (GHD) individuals remain incompletely understood. Earlier studies have been limited by the small size of cohorts studied. We have used the KIMS database to examine if a true difference exists between subjects who developed GHD in adult life (AO), and those who developed GHD in childhood (CO).
PATIENTS: A total of 1317 patients fulfilled the inclusion criteria, 1073 with AO GHD and 244 with CO GHD.
METHODS: Serum IGF-I concentrations were determined by a hydrochloric acid-ethanol extraction radioimmunoassay method using synthetic IGF-I for labelling. The reference range was calculated using normative data from healthy Swedish individuals.
RESULTS: A total of 86% of patients with CO GHD but only 52% of patients with AO GHD had IGF-I SDS below -2 SDS. The CO cohort had a lower IGF-I SDS (-4.69 vs. -2.24, P < 0.0001), a smaller body mass index (BMI; 26.6 vs. 28.6 kg/m2, P < 0.0001) and waist-hip ratio (WHR; 0.90 vs. 0.92 P < 0.001) than the AO cohort. A stepwise multiple linear regression was performed to examine the principal determinants of IGF-I SDS. Age at onset of GHD was the most important determinant of IGF-I SDS, contributing 17% towards the variability of IGF-I SDS. Timing of onset, gender, BMI, and number of pituitary hormone deficiencies other than GH deficiency were also significant determinants of IGF-I SDS.
CONCLUSION: Whilst age at onset of GHD was the most important determinant of IGF-I SDS, individuals with CO GHD had values on average 1.43 lower than those with AO GHD, all other factors being equal. Potential explanations include differences in GH secretory patterns, variation in body composition, and/or suboptimal treatment of GHD in childhood.

PMID 14974921  Clin Endocrinol (Oxf). 2003 Dec;59(6):773-8. doi: 10.10・・・
著者: Takara L Stanley, Meghan N Feldpausch, Caitlin A Murphy, Steven K Grinspoon, Hideo Makimura
雑誌名: Growth Horm IGF Res. 2014 Feb;24(1):10-5. doi: 10.1016/j.ghir.2013.11.001. Epub 2013 Nov 15.
Abstract/Text OBJECTIVE: To investigate the concordance/discordance of IGF-1 and peak stimulated GH in identifying subjects with reduced GH secretion and to determine the physiological significance of any discordance in obese subjects.
DESIGN, PATIENTS AND METHODS: 95 obese and 43 normal weight men and women underwent measurement of IGF-1 and GH stimulation testing with GH releasing hormone (GHRH)-arginine. Reduced IGF-1 and GH secretion were defined using pre-determined cut-points. Cardiovascular disease risk was determined by measuring carotid intima-media thickness (cIMT). In a second study, IGF-1 was measured in 52 obese men and women who underwent GH stimulation testing and overnight frequent blood sampling. The association of IGF-1 and peak stimulated GH with parameters of endogenous GH secretion was assessed.
RESULTS: 60% of obese subjects had normal IGF-1 and peak stimulated GH while 8.4% of obese subjects had reduced IGF-1 and GH secretion. Discordance rate for IGF-1 and peak GH was 31.6%. Subjects with both low IGF-1 and low peak GH had the highest cIMT, while subjects with both normal IGF-1 and peak GH had the lowest cIMT. Subjects with reduction in either IGF-1 or peak GH, had intermediate cIMT (P=0.02). IGF-1 and peak stimulated GH were associated with maximum and mean overnight serum GH and GH AUC as well as maximum peak mass and median pulse mass. Peak stimulated GH, but not IGF-1, was also associated with nadir overnight serum GH concentration and basal GH secretion.
CONCLUSION: Peak stimulated GH and IGF-1 demonstrate significant discordance in identification of subjects with reduced GH secretion in obesity. Subjects with reduction of either IGF-1 or peak GH had higher cIMT compared to subjects with both normal IGF-1 and peak GH. Subjects with reductions in both IGF-1 and peak GH had the highest cIMT. Peak GH, compared to IGF-1, has broader associations with various parameters of endogenous GH secretion which support its utility in identifying those with reduced GH secretion.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 24291224  Growth Horm IGF Res. 2014 Feb;24(1):10-5. doi: 10.1016/・・・
著者: D M Cook, W H Ludlam, M B Cook
雑誌名: J Clin Endocrinol Metab. 1999 Nov;84(11):3956-60. doi: 10.1210/jcem.84.11.6113.
Abstract/Text We prospectively studied two groups of GH-deficient patients during GH therapy based upon exposure of the liver to elevated (oral estrogen) or not elevated (endogenous or transdermal) sources of estrogen. We wondered whether higher concentrations of estrogen at the liver level (oral estrogen) might inhibit insulin-like growth factor I (IGF-I) secretion and alter exogenous GH requirements. In this study we compared GH replacement requirements in these two groups of women as well as with GH-treated adult hypopituitary males. The final GH dose was based upon maintenance IGF-I levels in the mid- to high normal range adjusted for age and sex or symptom tolerance. Each group [women taking oral estrogen (n = 12), women not taking oral estrogen (n = 13), and men (n = 12)] was similar in age and final IGF-I concentration. Women taking oral estrogen required 10.6 +/- 0.7 microg/kg x day or 867 +/- 45 microg/day GH, women not taking oral estrogen required 5.0 +/- 0.7 microg/kg x day or 424 +/- 57 microg/day, and men required 4.1 +/- 0.6 microg/kg x day or 376 +/- 49 microg/day to achieve similar IGF-I concentrations. GH requirements in men were not different from those in women not taking oral estrogen, but the GH requirements in both groups were significantly different from GH requirements in women taking oral estrogen. These observations may be useful in anticipating appropriate starting and final doses of GH in adult hypopituitary patients.

PMID 10566634  J Clin Endocrinol Metab. 1999 Nov;84(11):3956-60. doi: ・・・
著者: Silvia Porretti, Claudia Giavoli, Cristina Ronchi, Gaetano Lombardi, Marco Zaccaria, Domenico Valle, Maura Arosio, Paolo Beck-Peccoz
雑誌名: J Clin Endocrinol Metab. 2002 May;87(5):2042-5. doi: 10.1210/jcem.87.5.8479.
Abstract/Text The effect on thyroid function of GH administration to 66 adult patients with severe GH deficiency was studied. Seventeen patients were euthyroid, and 49 had central hypothyroidism and were adequately treated with L-T(4). Forty patients were assigned to a low recombinant human GH (rhGH) regimen (3 microg/kg body wt.d for 3 months followed by 6 microg/kg body wt.d for another 3 months) and 26 to a higher one (6 microg/kg body wt.d for 3 months followed by 12 microg/kg body wt.d for another 3 months). Serum IGF-I, TSH, free T(4) (FT(4)), free T(3) (FT(3)), reverse T(3), T(4)-binding globulin, and antithyroid autoantibody (TgAb and TPOAb) were measured in basal condition and after 3 and 6 months of therapy. Normalization of IGF-I levels was obtained after 6-month rhGH treatment in 67% of patients, independently from the dose, whereas a significant reduction in FT(4) and reverse T(3) levels was recorded (P < 0.01), without variations in all the other parameters studied, including serum TSH, FT(3), and T(4)-binding globulin circulating levels. Antithyroid autoantibodies were detected in 11 of 66 patients (16.6%). Eight of 17 (47%) euthyroid subjects and 9 of 49 (18.3%) central hypothyroid patients, despite adequate substitution at baseline, showed FT(4) levels under the normal range at the end of the study. Altogether, 17 of 66 patients (25.7%) worsened their thyroid function. This study shows that GH deficiency masks in a consistent number of adult patients a state of central hypothyroidism. Therefore, during rhGH treatment, a careful monitoring of thyroid function is mandatory to start or adjust L-T(4) substitutive therapy.

PMID 11994338  J Clin Endocrinol Metab. 2002 May;87(5):2042-5. doi: 10・・・
著者: Christa C van Bunderen, I Caroline van Nieuwpoort, Lucia I Arwert, Martijn W Heymans, Anton A M Franken, Hans P F Koppeschaar, Aart J van der Lely, Madeleine L Drent
雑誌名: J Clin Endocrinol Metab. 2011 Oct;96(10):3151-9. doi: 10.1210/jc.2011-1215. Epub 2011 Aug 17.
Abstract/Text CONTEXT: Adults with GH deficiency (GHD) have a decreased life expectancy. The effect of GH treatment on mortality remains to be established.
OBJECTIVE: This nationwide cohort study investigates the effect of GH treatment on all-cause and cause-specific mortality and analyzes patient characteristics influencing mortality in GHD adults.
DESIGN, SETTING, AND PATIENTS: Patients in the Dutch National Registry of Growth Hormone Treatment in Adults were retrospectively monitored (1985-2009) and subdivided into treatment (n = 2229), primary (untreated, n = 109), and secondary control (partly treated, n = 356) groups.
MAIN OUTCOME MEASURES: Standardized mortality ratios (SMR) were calculated for all-cause, malignancy, and cardiovascular disease (CVD) mortality. Expected mortality was obtained from cause, sex, calendar year, and age-specific death rates from national death and population counts.
RESULTS: In the treatment group, 95 patients died compared to 74.6 expected [SMR 1.27 (95% confidence interval, 1.04-1.56)]. Mortality was higher in women than in men. After exclusion of high-risk patients, the SMR for CVD mortality remained increased in women. Mortality due to malignancies was not elevated. In the control groups mortality was not different from the background population. Univariate analyses demonstrated sex, GHD onset, age, and underlying diagnosis as influencing factors.
CONCLUSIONS: GHD men receiving GH treatment have a mortality rate not different from the background population. In women, after exclusion of high-risk patients, mortality was not different from the background population except for CVD. Mortality due to malignancies was not elevated in adults receiving GH treatment. Next to gender, the heterogeneous etiology is of influence on mortality in GHD adults with GH treatment.

PMID 21849531  J Clin Endocrinol Metab. 2011 Oct;96(10):3151-9. doi: 1・・・
著者: Kim M J A Claessen, Natasha M Appelman-Dijkstra, Desirée M M M Adoptie, Ferdinand Roelfsema, Johannes W A Smit, Nienke R Biermasz, Alberto M Pereira
雑誌名: J Clin Endocrinol Metab. 2013 Jan;98(1):352-61. doi: 10.1210/jc.2012-2940. Epub 2012 Nov 15.
Abstract/Text BACKGROUND: The metabolic effects of recombinant human GH (rhGH) therapy in adults are well-documented in the short term. The effects of long-term rhGH therapy beyond 5 yr on metabolic parameters are presently unknown.
OBJECTIVE: The aim of the study was to evaluate the long-term effects of rhGH treatment on biochemical and anthropometric parameters in a large cohort of GH-deficient adults.
METHODS: Ninety-eight GH-deficient adult patients treated with rhGH for at least 10 yr were included (mean age, 59.4 yr; 50% female). Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, anthropometric parameters, IGF-I, and glucose were evaluated at baseline and after 5, 10, and 15 yr of treatment. In addition, the prevalence of the metabolic syndrome (MS) and the incidence of cardiovascular events were assessed.
RESULTS: Total cholesterol and low-density lipoprotein cholesterol concentrations were lower, and high-density lipoprotein cholesterol levels were significantly higher during long-term rhGH replacement when compared to baseline (all P < 0.001). Both waist circumference (P < 0.001) and body mass index (P = 0.018) were significantly higher after 10 yr, as were fasting plasma glucose levels (P < 0.001). No significant changes were observed in triglycerides, waist-to-hip ratio, and blood pressure during follow-up. In the subset of patients with 15-yr rhGH treatment (n = 43), generally similar metabolic effects were found. MS prevalence was increased after 10 yr of rhGH treatment (57.1 vs. 32.7%; P < 0.001), especially in males (69.4 vs. 32.7%; P < 0.001).
CONCLUSION: Despite improvement of several cardiovascular risk factors, MS prevalence increased significantly during rhGH treatment. The effect of long-term rhGH treatment on overall cardiovascular risk profile needs to be established in a larger cohort.

PMID 23162104  J Clin Endocrinol Metab. 2013 Jan;98(1):352-61. doi: 10・・・
著者: M Pfeifer, R Verhovec, B Zizek, J Prezelj, P Poredos, R N Clayton
雑誌名: J Clin Endocrinol Metab. 1999 Feb;84(2):453-7. doi: 10.1210/jcem.84.2.5456.
Abstract/Text Hypopituitary patients have increased mortality from vascular disease, and in these patients, early markers of atherosclerosis [increased carotid artery intima-media thickness (IMT) and reduced distensibility] are more prevalent. As GH replacement can reverse some risk factors of atherosclerosis, the present study examined the effect of GH treatment on morphological and functional changes in the carotid and brachial arteries of GH-deficient (GHD) adults. Eleven GHD hypopituitary men (24-49 yr old) were treated with recombinant human GH (0.018 U/kg BW x day) for 18 months. IMT of the common carotid artery (CCA) and the carotid bifurcation (CB), and flow-mediated endothelium-dependent dilation (EDD) of the brachial artery were measured by B mode ultrasound before and at 3, 6, 12, and 18 months of treatment, and values were compared with those in 12 age-matched control men. Serum concentrations of lipids, lipoprotein(a), insulin-like growth factor I (IGF-I), and IGF-binding protein-3 (IGFBP-3) were also measured. In GHD men before treatment the IMTs of the CCA [mean(SD), 0.67(0.05) mm] and CB [0.75(0.04) mm] were significantly greater (P < 0.001) than those in control men [0.52(0.07) and 0.65(0.07) mm, respectively]. GH treatment normalized the IMT of the CCA by 6 months [0.53(0.04) mm] and that of the CB by 3 months [0.68(0.05) mm]. The IMT of the carotid artery (CCA and CB) was negatively correlated with serum IGF-I (r = -0.53; P < 0.0001). There was a significant improvement in flow-mediated EDD of the brachial artery at 3 months, which was sustained at 6 and 18 months of GH treatment (P < 0.05). GH treatment increased high density lipoprotein cholesterol at 3 and 6 months, but did not reduce total or low density lipoprotein cholesterol and was without effect on lipoprotein(a). There was no correlation between plasma lipids and changes in IMT or EDD of the arteries examined. In conclusion, GH treatment of hypopituitary GHD men reverses early morphological and functional atherosclerotic changes in major arteries and, if maintained, may reduce vascular morbidity and mortality. GH seems to act via IGF-I, which is known to have important effects on endothelial cell function.

PMID 10022400  J Clin Endocrinol Metab. 1999 Feb;84(2):453-7. doi: 10.・・・
著者: Andrew R Hoffman, Joyce E Kuntze, Joyce Baptista, Howard B A Baum, Gerhard P Baumann, Beverly M K Biller, Richard V Clark, David Cook, Silvio E Inzucchi, David Kleinberg, Anne Klibanski, Lawrence S Phillips, E Chester Ridgway, Richard J Robbins, Janet Schlechte, Meeta Sharma, Michael O Thorner, Mary Lee Vance
雑誌名: J Clin Endocrinol Metab. 2004 May;89(5):2048-56. doi: 10.1210/jc.2003-030346.
Abstract/Text Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.

PMID 15126520  J Clin Endocrinol Metab. 2004 May;89(5):2048-56. doi: 1・・・
著者: B A Bengtsson, R Abs, H Bennmarker, J P Monson, U Feldt-Rasmussen, E Hernberg-Stahl, B Westberg, P Wilton, C Wüster
雑誌名: J Clin Endocrinol Metab. 1999 Nov;84(11):3929-35. doi: 10.1210/jcem.84.11.6088.
Abstract/Text Data from 665 adults with GH deficiency (GHD; 332 women; 169 childhood-onset GHD; mean age, 44 yr) were analyzed to determine the efficacy of and individual responsiveness to GH replacement therapy. GH replacement was started at enrolment into KIMS (Pharmacia & Upjohn, Inc. International Metabolic Database). Mean maintenance doses of GH after 6 and 12 months were 0.43 and 0.53 mg/day (1.3 and 1.6 IU/day) for men and women, respectively. Serum insulin-like growth factor I (IGF-I) SD score increased from -2.2 and -4.2 in men and women, respectively, to 1.8 and -0.9 at 6 months and 0.8 and -0.7 at 12 months. The waist/hip ratio decreased after 6 and 12 months, with the changes more pronounced in men. The waist/hip ratio was not influenced by age of onset of GHD, severity of hypopituitarism, or gonadal status. Total cholesterol decreased significantly in men, and high density lipoprotein cholesterol increased in women. Systolic blood pressure was unchanged during GH therapy, but diastolic blood pressure decreased in women. Quality of life, determined by a specific questionnaire for assessment of GHD in adults, improved after 6 and 12 months of GH therapy; this was more pronounced in adult-onset than in childhood-onset GHD, but was not influenced by gender, severity of hypopituitarism, or gonadal status. In 80% of patients, the starting dose of GH was 0.27 mg/day or less. This and the absence of a correlation between body weight and change in IGF-I were consistent with a dose-titration approach, which would tend to obscure individual variations in responses (determined by IGF-I levels). Nonetheless, the increase in IGF-I was significantly higher in men than in women on similar mean GH doses. Weak correlations were observed between the maintenance dose of GH and the change in IGF-I in men and women receiving sex steroid replacement, but not in patients with untreated hypogonadism or an intact gonadotropin reserve. Similarly, the increment in IGF-I was not related to the severity of GHD, as determined by the number of additional pituitary hormone deficiencies. Differences in IGF-I generation may partly explain the gender differences in reduction of central adiposity. These data highlight the value of large longitudinal surveillance databases in defining the optimum dose regimen for GH replacement and indicate that women may need a higher replacement dose of GH than men.

PMID 10566630  J Clin Endocrinol Metab. 1999 Nov;84(11):3929-35. doi: ・・・
著者: G Johannsson, T Rosén, B A Bengtsson
雑誌名: Clin Endocrinol (Oxf). 1997 Nov;47(5):571-81.
Abstract/Text OBJECTIVE: Until now, GH treatment in GH-deficient adults has employed dose schedules of GH based on body weight or body surface area and has ignored individual responsiveness to GH. This trial has studied the effects of an individualized GH dose adjusted to match a combination of clinical response, normalization of serum IGF-I concentration and body composition.
DESIGN AND PATIENTS: Two closely-matched groups, each comprising 30 GH-deficient adults, 38 men and 22 women aged 48 years, were treated with GH for 12 months. The high dose (HD) group received a target dose of 12 micrograms/kg per day and the individualized dose (ID) group received an initial daily GH dose of 0.17 or 0.33 mg per day (0.5 and 1 IU, respectively), independent of body weight, with dose adjustments thereafter.
MEASUREMENTS: Serum concentrations of IGF-I, lipoprotein(a), insulin, calcium, intact PTH, osteocalcin and blood glucose were measured. Body composition was determined according to a 4-compartment model using total body potassium and tritiated water as input variables. Total body nitrogen was measured by in vivo neutron activation and total body bone mineral content by dual energy X-ray absorptiometry.
RESULTS: At 12 months, the daily dose of GH was 0.55 +/- 0.03 mg and 0.45 +/- 0.03 mg in the HD and ID groups, respectively (P < 0.05). In the HD group, the mean serum IGF-I increased to levels well above the predicted level, while in the ID group the mean serum IGF-I normalized. Side-effects were experienced by 70% of the subjects in the HD group and by 30% in the ID group (P < 0.001). A similar response to GH in terms of body composition, glucose homeostasis, lipoprotein(a) and blood pressure was obtained in both treatment groups. However, the treatment response in terms of serum calcium, intact PTH and osteocalcin was more marked in the HD group.
CONCLUSIONS: Similar efficacy, with a lower dose of GH and fewer side-effects, was obtained by considering individual responsiveness to GH as compared to higher doses of GH adjusted to match body weight.

PMID 9425397  Clin Endocrinol (Oxf). 1997 Nov;47(5):571-81.
著者: Vera Popovic, Anders F Mattsson, Rolf C Gaillard, Patrick Wilton, Maria Koltowska-Häggström, Michael B Ranke
雑誌名: J Clin Endocrinol Metab. 2010 Sep;95(9):4449-54. doi: 10.1210/jc.2010-0287. Epub 2010 Jul 7.
Abstract/Text CONTEXT: The association between IGFs and cancer in adults with GH deficiency (GHD) receiving GH replacement requires investigation.
OBJECTIVE: The objective was to examine the association between IGF-I, IGF-binding protein 2 (IGFBP-2), and IGFBP-3 SD scores (SDSs) in GH-deficient adults receiving GH therapy and the occurrence of de novo malignancies.
DESIGN: Serum IGF-I, IGFBP-2, and IGFBP-3 levels in GH-deficient patients who developed a malignancy since receiving GH were compared with patients with idiopathic GHD but without malignancy. Measurements were related to age-, sex-, and body mass index-specific SDS reference regions.
SETTING: The setting included the KIMS (the Pfizer International Metabolic Database).
PATIENTS: One hundred patients with de novo malignancy during GH therapy were compared with 325 patients with idiopathic GHD without malignancy.
INTERVENTION(S): Serum samples were obtained as close as possible to the diagnosis of malignancy, or after approximately 2 yr of GH replacement in KIMS.
MAIN OUTCOME MEASURES: Associations between relative risk (RR) of malignancy and IGF-I, IGFBP-2, and IGFBP-3 SDSs were assessed in multiple log-linear Poisson working regression models, controlling for age, sex, onset of GHD, and GH naivety at KIMS entry.
RESULTS: No association between IGF-I SDSs and RR was observed (P = 0.48). Increasing IGFBP-2 and IGFBP-3 SDSs were associated with increasing RRs [18% per unit IGFBP-2 SDSs (95% confidence interval, 7-30%; P = 0.0006), 13% per unit IGFBP-3 SDS (2-26%; P = 0.01)].
CONCLUSIONS: IGF-I levels targeted to within normal age-related reference ranges during GH replacement were not associated with the occurrence of malignancies. Higher IGFBP-2 and/or IGFBP-3 SDSs may be associated with increased cancer risk.

PMID 20610598  J Clin Endocrinol Metab. 2010 Sep;95(9):4449-54. doi: 1・・・

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