Tsuyoshi Isojima, Akira Shimatsu, Susumu Yokoya, Kazuo Chihara, Toshiaki Tanaka, Naomi Hizuka, Akira Teramoto, Ke-ita Tatsumi, Katsuhiko Tachibana, Noriyuki Katsumata, Reiko Horikawa
Standardized centile curves and reference intervals of serum insulin-like growth factor-I (IGF-I) levels in a normal Japanese population using the LMS method.
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.
M Tauber, P Moulin, C Pienkowski, B Jouret, P Rochiccioli
Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment.
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.
Ken K Y Ho, 2007 GH Deficiency Consensus Workshop Participants
Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia.
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.
Mark E Molitch, David R Clemmons, Saul Malozowski, George R Merriam, Mary Lee Vance, Endocrine Society
Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
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.
Harald Jörn Schneider, Ilonka Kreitschmann-Andermahr, Ezio Ghigo, Günter Karl Stalla, Amar Agha
Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review.
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.
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
Consensus guidelines on screening for hypopituitarism following traumatic brain injury.
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.
Catherine A Lissett, Peter Jönsson, John P Monson, Stephen M Shalet, KIMS International Board
Determinants of IGF-I status in a large cohort of growth hormone-deficient (GHD) subjects: the role of timing of onset of GHD.
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.
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） [Internet]. 日本内分泌学会雑誌. 2019. p. 95 Suppl, p36-39. Available from: https://www.jstage.jst.go.jp/article/endocrine/95/S.May/95_1/_pdf/-char/ja
Takara L Stanley, Meghan N Feldpausch, Caitlin A Murphy, Steven K Grinspoon, Hideo Makimura
Discordance of IGF-1 and GH stimulation testing for altered GH secretion in obesity.
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.
D M Cook, W H Ludlam, M B Cook
Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults.
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.
Silvia Porretti, Claudia Giavoli, Cristina Ronchi, Gaetano Lombardi, Marco Zaccaria, Domenico Valle, Maura Arosio, Paolo Beck-Peccoz
Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory?
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.
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
Does growth hormone replacement therapy reduce mortality in adults with growth hormone deficiency? Data from the Dutch National Registry of Growth Hormone Treatment in adults.
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.
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
Metabolic profile in growth hormone-deficient (GHD) adults after long-term recombinant human growth hormone (rhGH) therapy.
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.
M Pfeifer, R Verhovec, B Zizek, J Prezelj, P Poredos, R N Clayton
Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults.
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.
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
Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial.
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.
B A Bengtsson, R Abs, H Bennmarker, J P Monson, U Feldt-Rasmussen, E Hernberg-Stahl, B Westberg, P Wilton, C Wüster
The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board.
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.
G Johannsson, T Rosén, B A Bengtsson
Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults.
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.
Vera Popovic, Anders F Mattsson, Rolf C Gaillard, Patrick Wilton, Maria Koltowska-Häggström, Michael B Ranke
Serum insulin-like growth factor I (IGF-I), IGF-binding proteins 2 and 3, and the risk for development of malignancies in adults with growth hormone (GH) deficiency treated with GH: data from KIMS (Pfizer International Metabolic Database).
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.
