Wednesday, March 31, 2010

Primary adrenal hypercortisolism: minimally invasive surgical treatment or medical therapy? A retrospective study with long-term follow-up evaluation

PDF (252.0 KB) | HTML | Free Preview

Primary adrenal hypercortisolism: minimally invasive surgical treatment or medical therapy? A retrospective study with long-term follow-up evaluation

Mario Guerrieri1, Roberto Campagnacci1 Contact 
Information, Andrea Patrizi1, Chiara Romiti1, Giorgio Arnaldi2 and Marco Boscaro2

(1)
Clinica di Chirurgia Generale e Metodologia Chirurgica, Università Politecnica delle Marche-Ospedali Riuniti, via Conca 1, 60121 Ancona, Italy

(2)
Clinica di Endocrinologia, Università Politecnica delle Marche-Ospedali Riuniti, via Conca 1, 60121 Ancona, Italy

Received: 6 November 2009  Accepted: 29 January 2010  Published online: 25 March 2010

Abstract

Background

Because the most suitable management of subclinical Cushing syndrome (SCS, which involves hypersecretion of cortisol without clinically evident disease) still is undefined, the current study aimed to compare retrospectively the outcome for a cohort of patients treated by medical therapy or laparoscopic adrenalectomy (LA).

Methods

Over a 12-year period, 47 patients with SCS have been treated by means of LA (19 patients, group A) or medical therapy (28 patients, group B). Group A consisted of 15 women and 4 men with a mean age of 54.8 years. Eight patients had a left adrenal mass, whereas nine had a right adrenal mass, and one patient had bilateral lesion. Group B was composed of 18 women and 10 men with a mean age of 57.8 years. Of these patients, 14 had a left adrenal lesion, 12 had a right adrenal lesion, and 1 had bilateral lesion. The patients were followed up for a mean 4 years (range, 1–11 years) by both an endocrinologist and a surgeon.

Results

In group A, hypertension improved for 66.3% of the patients; body mass index (BMI) decreased for 47.4%; and hyperlipidemia based on high-density lypoproteins (HDL) cholesterol, total cholesterol ratio, and triglyceridemic concentration improved for 63.2% of the patients. No changes in bone parameters were seen after surgery in SCS patients with osteoporosis. Some patients in group B, during their long-term medical therapy, experienced worsening hypertension (14.2%), hyperlipidemia (17.8%), and diabetes mellitus (8%).

Conclusions

This retrospective study focused on a cohort of patients with SCS. Their medium long-term follow-up evaluation showed that LA is better than medical therapy for treating this condition, especially by reducing the cardiovascular risk (hypertension-hyperlipidemia).

Keywords Cushing syndrome - Laparoscopic adrenalectomy - Subclinical Cushing


Contact 
Information
Roberto Campagnacci
Email: rcampagnacci@libero.it

Fulltext Preview (Small, Large)

Image of the first page of the fulltext

From http://www.springerlink.com/content/g72h7p32vx181217/

Is There Value in Routine Screening for Cushing's Syndrome in Patients with Diabetes?

Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-2453

K. Mullan, N. Black, A. Thiraviaraj, P. M. Bell, C. Burgess, S. J. Hunter, D. R. McCance, H. Leslie, B. Sheridan,  and A. B. Atkinson*

Regional Centre for Endocrinology and Diabetes (K.M., N.B., A.T., P.M.B., S.J.H., D.R.M., A.B.A.), and Regional Endocrine Laboratory (C.B., H.L., B.S.), Royal Victoria Hospital, Belfast BT12 6BA, United Kingdom

* To whom correspondence should be addressed. E-mail: brew.atkinson@belfasttrust.hscni.net..

Context: Subclinical Cushing's syndrome has been described among diabetic populations in recent years, but no consensus has emerged about the value of screening.

Methods: We enrolled 201 consecutive patients attending our diabetes clinic and 79 controls. Patients with at least two of the following three criteria were offered screening using a 2300 h salivary cortisol test: glycosylated hemoglobin of at least 7%, body mass index of at least 25 kg/m2, and a history of hypertension or blood pressure of at least 140/90 mm Hg. Results are expressed as mean ± SEM.

Results: Mean nighttime salivary cortisol levels were similar in the two groups (8.5 ± 1.0 nmol/liter for diabetic patients vs. 5.8 ± 1.0 nmol/liter for controls). Forty-seven patients (23%) had a value of at least 10 nmol/liter, which was set as a conservative threshold above which further investigation would be performed. Thirty-five (75%) agreed to further testing with a 1-mg overnight dexamethasone test. Of the remaining 12 patients, 10 were followed up clinically for at least 1 yr, and no evidence was found of the syndrome evolving. In 28 patients, serum cortisol suppressed to 60 nmol/liter or less. Of the seven patients who failed this test, four agreed to a 2 mg/d 48-h dexamethasone test, with serum cortisol suppressing to 60 nmol/liter or less in all four. Three declined this test but had normal 24-h urinary free cortisol levels. No patient had clinical features of hypercortisolism.

Conclusions: The 1–3% detection rates of three recently published series have not been realized at our center where we studied a group using criteria making patients more likely to have hypercortisolism. Our results do not support the validity of screening patients without clinical features of Cushing's syndrome in the diabetes clinic.

http://jcem.endojournals.org/cgi/content/abstract/jc.2009-2453v1

Monday, March 29, 2010

Trends in adrenalectomy: a recent national review

PDF (269.4 KB) | HTML | Free Preview

Trends in adrenalectomy: a recent national review

Melissa M. Murphy1 Contact 
Information, Elan R. Witkowski1, Sing Chau Ng1, Theodore P. McDade1, Joshua S. Hill1, Anne C. Larkin1, Giles F. Whalen1, Demetrius E. Litwin1 and Jennifer F. Tseng1 Contact 
Information

(1)
Department of Surgery, Surgical Outcomes Analysis and Research (SOAR), University of Massachusetts Medical School, 55 Lake Avenue North, Suite S3-752, Worcester, MA 01655, USA

Received: 20 May 2009  Accepted: 26 February 2010  Published online: 25 March 2010

Abstract

Background

Adrenalectomy remains the definitive therapy for most adrenal neoplasms. Introduced in the 1990s, laparoscopic adrenalectomy is reported to have lower associated morbidity and mortality. This study aimed to evaluate national adrenalectomy trends, including major postoperative complications and perioperative mortality.

 

Methods

The Nationwide Inpatient Sample was queried to identify all adrenalectomies performed during 1998–2006. Univariate and multivariate logistic regression were performed, with adjustments for patient age, sex, comorbidities, indication, year of surgery, laparoscopy, hospital teaching status, and hospital volume. Annual incidence, major in-hospital postoperative complications, and in-hospital mortality were evaluated.

 

Results

Using weighted national estimate, 40,363 patients with a mean age of 54 years were identified. Men made up 40% of these patients, and 77% of the patients were white. The majority of adrenalectomies (83%) were performed for benign disease. The annual volume of adrenalectomies increased from 3,241 in 1998 to 5,323 in 2006 (p < 0.0001, trend analysis). The overall in-hospital mortality was 1.1%, with no significant change. Advanced age (<45 years as the referent; ≥65 years: adjusted odds ratio [AOR], 4.10; 95%; confidence Interval [CI], 1.66–10.10) and patient comorbidities (Charlson score 0 as the referent; Charlson score ≥2: AOR, 4.33; 96% CI, 2.34–8.02) were independent predictors of in-hospital mortality. Indication, year, hospital teaching status, and hospital volume did not independently affect perioperative mortality. Major postoperative in-hospital complications occurred in 7.2% of the cohort, with a significant increasing trend (1998–2000 [5.9%] vs 2004–2006 [8.1%]; p < 0.0001, trend analysis). Patient comorbidities (Charlson score 0 as the referent; Charlson score ≥2: AOR, 4.77; 95% CI, 3.71–6.14), recent year of surgery (1998–2000 as the referent; 2004–2006: AOR, 1.40; 95% CI, 1.09–1.78), and benign disease (malignant disease as the referent; benign disease: AOR, 1.98; 95% CI, 1.55–2.53) were predictive of major postoperative complications at multivariable analyses, whereas laparoscopy was protective (no laparoscopy as the referent; laparoscopy: AOR, 0.62; 95% CI, 0.47–0.82).

 

Conclusion

Adrenalectomy is increasingly performed nationwide for both benign and malignant indications. In this study, whereas perioperative mortality remained low, major postoperative complications increased significantly.

Keywords Adrenalectomy - Complications - Mortality - Nationwide inpatient sample


Contact 
Information
Melissa M. Murphy
Email: melissa.murphy-smith@umassmemorial.org

Contact 
Information
Jennifer F. Tseng (Corresponding author)
Email: Jennifer.Tseng@umassmemorial.org

Fulltext Preview (Small, Large)

Image of the first page of the fulltext

From http://www.springerlink.com/content/h2j69247138788u8/

Friday, March 26, 2010

Effects of Cushing Disease on Bone Mineral Density in a Pediatric Population

Maya B. Lodish, MDabCorresponding Author Informationemail address, Hui-Pin Hsiao, MDac, Anastasios Serbis, MDa, Ninet Sinaii, PhD, MPHd, Anya Rothenbuhler, MDa, Margaret F. Keil, CRNPa, Sosipatros A. Boikos, MDa, James C. Reynolds, MDe, Constantine A. Stratakis, MD, DScab

Received 30 July 2009; received in revised form 19 October 2009; accepted 16 December 2009. published online 11 March 2010.
Corrected Proof

Objective

To evaluate bone mineral density (BMD) in children with Cushing disease before and after transphenoidal surgery (TSS).

Study design

Hologic dual-energy x-ray absorptiometry (DXA) scans of 35 children with Cushing disease were analyzed retrospectively. Sixteen of the 35 patients had follow-up DXA scans performed 13 to 18 months after TSS. BMD and bone mineral apparent density (BMAD) for lumbar spine (LS) L1 to L4 and femoral neck (FN) were calculated.

Results

Preoperatively, 38% and 23% of patients had osteopenia of the LS and FN, respectively. Both BMD and BMAD Z-scores of the LS were worse than those for the FN (–1.60 ± 1.37 versus –1.04 ± 1.19, P = .003), and (–1.90 ± 1.49 versus –0.06 ± 1.90, P < .001); postoperative improvement in BMD and BMAD were more pronounced in LS than in the FN (0.84 ± 0.88 versus 0.15 ± 0.62, P<.001; and 0.73 ± 1.13 versus –0.26 ± 1.21, P = .015). Pubertal stage, cortisol levels, and length of disease had no effect on BMD.

Conclusions

In children with Cushing disease, vertebral BMD was more severely affected than femoral BMD and this effect was independent of degree or duration of hypercortisolism. BMD for the LS improved significantly after TSS; osteopenia in this group may be reversible.

BMAD, Bone mineral apparent density, BMD, Bone mineral density, CS, Cushing syndrome, DXA, Dual-energy x-ray absorptiometry, FN, Femoral neck, GH, Growth hormone, GHD, Growth hormone deficiency, LS, Lumbar spine, TSS, Transphenoidal surgery, UFC, Urinary free cortisol

a Section on Endocrinology Genetics, Program on Developmental Endocrinology Genetics, National Institutes of Health, Bethesda, MD

b Pediatric Endocrinology Inter-Institute Training Program, National Institutes of Health, Bethesda, MD

c Department of Pediatrics, Kaohsiung Municipal HsiaoKang Hospital and College of Medicine, Kaohsiung Medical University, Taiwan

d Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD

e Department of Radiology, Nuclear Medicine Division, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD

Corresponding Author InformationReprint requests: Dr Maya Lodish, NICHD, NIH, Bldg 10, CRC (East Laboratories), Room 1-3330, 10 Center Dr, MSC 1103, Bethesda, MD 20892.

The authors have no financial relationships relevant to this article to disclose. Supported by the US National Institutes of Health, National Institute of Child Health and Human Development intramural project (Z01-HD-000642-04) (C.S.). The authors declare no conflicts of interest.

PII: S0022-3476(09)01256-6

doi:10.1016/j.jpeds.2009.12.027

© 2010 Mosby, Inc. All rights reserved.

Full Text at http://www.jpeds.com/article/PIIS0022347609012566/fulltext

Tuesday, March 23, 2010

Cushing’s syndrome: Why is diagnosis so difficult?

PDF (220.1 KB) | HTML | Free Preview

Cushing’s syndrome: Why is diagnosis so difficult?

David C. Aron1, 2, 3 Contact Information

(1) 
Division of Clinical and Molecular Endocrinology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA

(2) 
VA Health Services Research & Development Quality Enhancement Research Initiative Center for Implementation Practice and Research Support, Louis Stokes Cleveland VAMC, Cleveland, OH, USA

(3) 
Louis Stokes Department of Veterans Affairs Medical Center, Education Office 14 (W), 10701 East Blvd., Cleveland, OH 44106, USA

Published online: 9 March 2010

Abstract 

Practicing and perfecting the art of medicine demands recognition that uncertainty permeates all clinical decisions. When delivering clinical care, clinicians face a multiplicity of potential diagnoses, limitations in diagnostic capacity, and “sub-clinical” disease identified by tests rather than by clinical manifestations. In addition, clinicians must recognize the rapid changes in scientific knowledge needed to guide decisions. Cushing’s syndrome is one of several disorders in which there may be considerable difficulty and delay in diagnosis. This article describes a current model of clinical reasoning, some of its challenges, and the application of the principles of clinical epidemiology to meet some of those challenges.

Keywords  Cushing’s syndrome - Clinical decision making - Clinical epidemiology


Contact Information
David C. Aron
Email: david.aron@va.gov

Fulltext Preview (Small, Large)
Image of the first page of the fulltext

 

From http://www.springerlink.com/content/f61062403u1023x5/

Monday, March 22, 2010

Long-term unemployment associated with poorer health

Patients with long-term chronic conditions, such as Cushing’s disease or Klinefelter’s syndrome, appear to be at increased risk for long-term unemployment related to their disease.

Researchers compared unemployment rates with re-employment rates for 130 patients (81 women) aged 65 years or younger with Addison’s disease, Cushing’s disease, craniopharyngioma or Klinefelter’s syndrome. The researchers presented the results at the Annual Society for Endocrinology BES 2010 in Manchester, England.

Based on telephone questionnaires, 83 patients (63.8%) were employed at the time of diagnosis. However, 79 patients (60.8%) were later unemployed, related to their long-term chronic condition.

Seventy-seven patients (59.2%) reported being satisfied with their current working status and ability to work. Among those unemployed, nine of 53 patients (40.8%) said they would like to work but did not feel supported.

Although the study was small and did not include all chronic endocrine conditions, the researchers said data show a high rate of unemployment for this patient population.

“Long-term unemployment is a significant problem for people with chronic diseases,” John Wass, MD, professor of endocrinology at Oxford University and consultant endocrinologist at Oxford Radcliffe Hospitals, said in a press release. “More people should consider returning to work following diagnosis, and more doctors need to encourage and support their patients in this. While a return to work may not be suitable for all patients, it can significantly improve their well-being and quality of life.”

Wass J. Poster #116. Presented at: The Annual Society for Endocrinology BES meeting; March 15-18, 2010; Manchester, England.

From http://www.endocrinetoday.com/view.aspx?rid=62296

Friday, March 19, 2010

Magnetic Resonance Imaging and Pituitary Function in Children with Panhypopituitarism

Free Abstract Article (Fulltext) Article (PDF 148 KB)


Original Paper

Magnetic Resonance Imaging and Pituitary Function in Children with Panhypopituitarism
Guimei Li, Peng Shao, Xiaojun Sun, Qian Wang, Lijuan Zhang
Provincial Hospital Affiliated to Shandong University, Shandong, PR China

Address of Corresponding Author

Horm Res Paediatr 2010;73:205-209 (DOI: 10.1159/000284363)


 Key Words

  • Magnetic resonance imaging
  • Insulin-like growth factor-1
  • Multiple pituitary hormone
  • Panhypopituitarism

 Abstract

Background: To explore the relationship between magnetic resonance imaging (MRI) findings and multiple pituitary-target hormones in patients with panhypopituitarism or multiple pituitary hormone deficiency (MPHD).

Methods: 125 patients with MPHD (102 boys, MPHD group) and 90 age-, sex- and Tanner stage-matched normal children (control group) were enrolled. 96 of the patients with MPHD underwent MRI scans of the hypothalamic-pituitary area. The patients were subdivided into five stages according to their MRI findings. The serum concentrations of GH, IGF-1, FT4, TSH, ACTH, cortisol, FSH, LH, prolactin, testosterone and estradiol were measured in patients and in controls.

Results: MRI stage was significantly positively correlated with the number of pituitary hormone deficiencies (r = 0.9, p < 0.001). MRI stage was negatively correlated with peak GH, IGF-1, FT4, cortisol and anterior pituitary height (r = –0.43, –0.47, –0.67, –0.54, and –0.49, respectively, p < 0.01). Diabetes insipidus patients could be stratified according to their MRI stage; diabetes insipidus was found mainly in patients with absence of the posterior pituitary bright spot or small ectopic posterior pituitary bright spot on MRI.

Conclusion: An abnormal MRI finding is evidence of MPHD and, correspondingly, there is a noteworthy correlation between MRI and pituitary function.

Copyright © 2010 S. Karger AG, Basel

From http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=284363&Ausgabe=253980&ProduktNr=224036

A technical note on endonasal combined microscopic endoscopic with free head navigation technique of removal of pituitary adenomas

PDF (384.5 KB) | HTML | Free Preview | Supplemental Material

Original Article

A technical note on endonasal combined microscopic endoscopic with free head navigation technique of removal of pituitary adenomas

Ossama Al-Mefty1 Contact Information, Svetlana Pravdenkova1 and Cristian Gragnaniello1

(1) 
Department of Neurosurgery, University of Arkansas for Medical Sciences, 4301 W. Markham, #507, Little Rock, AR 72205, USA

Received: 11 December 2008  Revised: 9 June 2009  Accepted: 2 January 2010  Published online: 2 March 2010

Abstract 

Pituitary surgery exemplifies the continuous refinement of surgical techniques. The transsphenoidal approach is the approach of choice to treat most pituitary adenomas. We report here, as a technical note, an operative nuance that represents an encompassment of various technical steps that we utilize in our current surgery, including the corroboration of navigation system on a free head with combined use of endoscope and microscope techniques.

Electronic supplementary material  The online version of this article (doi:10.1007/s10143-010-0241-1) contains supplementary material, which is available to authorized users.

Keywords  Transsphenoidal surgery - Sellar tumors - Pituitary adenoma - Surgical technique - Microsurgery - Endonasal endoscopy - Neuronavigation - Minimal invasive surgery


Contact Information
Ossama Al-Mefty
Email: keelandamye@uams.edu

Fulltext Preview (Small, Large)
Image of the first page of the fulltext

 

From http://www.springerlink.com/content/t1737t72r73kxg22/

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Vita Birzniece, Udo Meinhardt, James Gibney, Gudmundur Johannsson, Robert C. Baxter, Markus J. Seibel, and Ken K. Y. Ho*

Garvan Institute of Medical Research and Department of Endocrinology (V.B., U.M., J.G., G.J., K.K.Y.H.), St. Vincent's Hospital, Sydney, NSW 2010, Australia; The University of New South Wales (K.K.Y.H.), Sydney, NSW 2052, Australia; Kolling Institute of Medical Research (R.C.B.), The University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065 Australia; and ANZAC Research Institute (M.J.S.), The University of Sydney at Concord, NSW 2139, Australia

* To whom correspondence should be addressed. E-mail: k.ho@garvan.org.au.

Context: The metabolic action of GH is attenuated by estrogens administered via the oral route. Selective estrogen receptor modulators lower IGF-I to a lesser degree than 17β-estradiol in GH-deficient women, and their effect on fat and protein metabolism is unknown.

Objective: The aim of the study was to compare the modulatory effects of 17β-estradiol and raloxifene, a selective estrogen receptor modulator, on the metabolic action of GH. Design: We conducted an open-label, two-group, randomized, two-period crossover study.

Patients and Intervention: Ten hypopituitary women received GH therapy alone (0.5 mg/d) and GH plus 17β-estradiol (E2; 2 mg/d). Eleven hypopituitary women received GH therapy alone and GH plus raloxifene (R; 60 mg/d). The treatment duration was 1 month, with a 4-wk washout period.

Main Outcome Measures: IGF-I, IGFBP-3, resting energy expenditure, and fat oxidation were quantified by indirect calorimetry. We measured whole body leucine turnover from which leucine rate of appearance and leucine incorporation into protein were estimated.

Results: GH significantly stimulated all outcome measures. During GH treatment, addition of R significantly reduced mean IGF-I but not IGFBP-3, whereas E2 reduced both IGF-I and IGFBP-3 levels. Cotreatment with R but not E2 significantly attenuated the stimulatory effects of GH on fat oxidation. There was a strong trend (P = 0.08) toward a greater reduction in leucine incorporation into protein after R compared to E2 cotreatment.

Conclusions: The modulatory effects of E2 and R at therapeutic doses on GH action are different. R during GH therapy exerts a greater inhibitory effect on lipid oxidation and protein anabolism compared to E2

From http://jcem.endojournals.org/cgi/content/abstract/jc.2009-2743v1

Friday, March 5, 2010

FDA approved somatropin injection pen for GH disorders

The FDA has approved somatropin pre-filled injection pens for the treatment of children and adults with growth hormone disorders.

Norditropin FlexPro (Novo Nordisk) has a user-friendly design and an audible click to confirm that the medication has left the pen. It requires no reconstitution and no loading of cartridges.

Study results indicate that 100% of patients found the injection pen easy to use, according to Novo Nordisk.

Somatropin is approved to treat children with growth failure caused by very low or no production of GH and in adults who do not produce enough GH. This product is also indicated for children who have short stature associated with Noonan and Turner syndromes and children with short stature born small for gestational age with no catch-up growth by age 2 to 4 years.

Norditropin FlexPro is available in 5 mg/1.5 mL, 10 mg/1.5 mL and 15 mg/1.5 mL pens. After initial use, the 5 mg/1.5 mL and 10 mg/1.5 mL pens may be left at room temperature for up to three weeks without risk for spoilage.

The product is contraindicated in people who have a critical illness caused by heart or stomach surgery, trauma or respiratory problems; Prader-Willi syndrome, severe obesity or breathing problems such as sleep apnea; cancer or other tumors; eye problems associated with diabetes; epiphyses; and allergies to any ingredients in the product.

The most common adverse events associated with include headache, muscle pain, joint stiffness, hyperglycemia, glucosuria, swollen hands and feet due to fluid retention and redness and itching at the injection side. Other more serious adverse events include reports of intracranial hypertension, worsening of scoliosis and slipped capital femoral epiphysis in children. Patients with Noonan and Turner syndromes should be closely monitored by health care professionals due to increased risk for congenital heart disease.

Health care professionals should be aware if patients also take glucocorticoid medication, thyroid hormone, insulin or other medicines for diabetes, oral estrogen replacement therapy or medicines that are metabolized by the liver, such as corticosteroids, sex steroids, anticonvulsants or cyclosporine.

Novo Nordisk introduced somatropin (Norditropin) in 1988 and the first pre-filled GH pen Norditropin NordiFlex in 2004.

The Norditropin FlexPro pen will be available in the second quarter of 2010, according to Novo Nordisk.

 

From http://www.endocrinetoday.com/view.aspx?rid=61590

Thursday, March 4, 2010

Measurement of human growth hormone by immunoassays: Current status, unsolved problems and clinical consequences

Martin BidlingmaierCorresponding Author Contact Information, 1, a, b, E-mail The Corresponding Author and Pamela U. Fredaa, b

a Endocrine Research Laboratories, Medizinische Klinik – Innenstadt, Ludwig-Maximilians University, Munich, Germany

b Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA

Received 16 September 2009; 

accepted 17 September 2009. 

Available online 8 October 2009.

Abstract

Measuring the concentration of growth hormone (GH) in blood samples taken during dynamic tests represents the basis for diagnosis of growth hormone related disorders, namely growth hormone deficiency and growth hormone excess. Today, a wide spectrum of immunoassays are in use, enabling rapid and sensitive determination of growth hormone concentrations in routine diagnostics. From a clinical point of view several difficulties exist with the use and interpretation of GH assay results in the assessment of GH related disorders: Many physiological factors such as fat mass, age and gender influence the outcome of dynamic tests, overall leading to significant inter-individual differences in GH responses. However, in addition to the physiological variability, considerable variability exists in GH assay results obtained by different immunoassays. Unfortunately, all the new technical advances in the field of GH measurement techniques have not reduced this methodological variability. To a large extent, the actual values reported for the GH concentration in a sample depend on the method used by the respective laboratory. Obviously, such discrepancies limit the applicability of consensus guidelines on diagnosis and treatment in clinical practice.

This review summarizes current practices for GH measurement with respect to the methods used, their limitations and the clinical consequences of the existing heterogeneity in GH immunoassay results.

Keywords: Growth hormone; Immunoassays; Standardization

Article Outline
1. Methods of GH measurement
2. Comparability of GH assay results
3. Factors leading to poor comparability of GH assay results
3.1. Molecular heterogeneity of the analyte
3.2. Reference preparations for GH assays
3.3. Impact of GHBP and other matrix components
4. Clinical consequences of poor comparability of GH assay results
5. Points for discussion
5.1. Issues related to the molecular heterogeneity of GH
5.1.1. Which GH isoform should be measured?
5.1.2. Is it possible to “translate” GH assay results from one assay to another?
5.2. Issues related to assay calibration
5.2.1. Which calibrator should be used for GH assays?
5.3. Issues related to assay validation and performance control
5.3.1. What information must be given for GH assays with respect to specificity and interference?
5.4. Issues related to the clinical interpretation of GH assay data
5.4.1. What are quality criteria for establishing cut off values?
5.4.2. Given the inherent differences between concentrations determined by different immunoassays – what can be done to improve reliability of applying guidelines and recommendations?
References

1. Methods of GH measurement
In recent decades several methods have been developed for the measurement of growth hormone (GH) activity or concentration in biological fluids. From the very early demonstrations of GH activity in human plasma [1] and [2] to the more recent development of bioassays or radioreceptor assays [3] and [4], there have been attempts to not only measure the presence (concentration), but also the activity of the GH molecules in a patient’s sample. However, the latter methodologies never reached a distribution among clinical laboratories comparable to that of the immunoassays. The main advantage of immunoassays is that they allow large series of samples to be easily analysed very quickly, an important factor for the clinical laboratory given the increased demand for GH determinations.

In the years following the description of the first radioimmunoassay for insulin [5], several radioactive GH assays based on the same immunological principle were reported [6], [7], [8] and [9]. Later, enzyme immunoassays [10] and other non-radioactive immunoassays [11] were also developed for the measurement of GH. Today, most of the automated high-throughput analysers in routine use in clinical laboratories utilize chemiluminescence assays to measure GH. In addition to changing the label from radioactivity to other reporting systems, the evolution of GH assays has also been characterized by a switch from competitive immunoassays based on polyclonal antisera to sandwich type immunoassays employing monoclonal antibodies. Competitive assays use labelled GH as a tracer, which competes with the unlabelled GH in the sample for binding to an antibody. The higher the concentration of GH in a sample, the less likely the labelled tracer GH will bind to the antibody. Therefore, there is an inverse correlation between signal intensity and concentration of the analyte. Frequently employing polyclonal antibodies, these assays typically exhibited a lower detection limit in a range between 0.5–1.0 μg/L. In contrast, today’s sandwich type immunoassays for GH employ two antibodies directed against different epitopes on the surface of the GH molecule. One antibody is used to capture the GH molecules in a sample, whereas the second antibody is labelled and used to translate the bound GH molecule into a signal. The intensity of the signal obtained is proportional to the amount of GH present in the samples. Sandwich type assays for GH are available with various labels (radioactivity, enzyme linked and fluorescence), but most automated assay systems currently in use in large laboratories are based on chemiluminescence. An overview on widely used commercially available GH assays is given in Table 1. These immunoassays usually have a sensitivity of around 0.2 μg/L or better, and the most sensitive ones have been reported to reach a sensitivity below 0.002 μg/L [12].

Table 1.

Characteristics of commonly used commercial assays for GH (according to manufacturers instructions/kit inserts available to the authors or according to published data). Calibration has changed for several assays in recent years, and the process is ongoing. Thus, the information provided might not be up to date for all assay lots on the market, and also not for all countries. Furthermore, the list of assays is not complete. Additional hGH assays exist, including an unknown number of in-house assays.

Manufacturer
Name
Assay principle
Calibration
Isoform specificity
Recommended sample material
Comment

Siemens
Immulite 2000/2500 hGH
Automated immunometric assay (mAb + pAb), chemiluminescence
98/574/80/505
Not provided
Serum
Calibrator changed to 98/574 since lot 206 in most European countries. Calibrator 80/505 in the US

DiaSorin
Liaison hGH
Automated immunometric assay (mAb + pAb), chemiluminescence
98/574
Not provided
Serum

Beckmann–Coulter
Access ultrasensitive hGH
Automated immunometric assay (pAb + mAb), chemiluminescence
98/574/80/505
20 kD < 4%
Serum
Calibrator 80/505 according to [81]

IDS
iSys hGH
Automated immunometric assay (mAb + mAb), chemiluminescence
98/574
20 kD < 2%
Serum, plasma (heparin, citrate)
Information from manufacturers flyer, assay available 9/2009

Perkin–Elmer (Wallac)
DELFIA hGH
Immunometric assay (mAb + mAb), time-resolved fluorescence
80/505
22 kD specific
Serum, plasma (heparin)

BioSource
hGH IRMA
Immunometric assay (mAb + mAb), radioactive
98/574
Not provided
Serum, plasma (heparin, EDTA)

Adaltis
hGH Bridge
Immunometric assay, radioactive
80/505/88/624
Not provided
Serum
Provides standard concentrations for both calibrators

CisBio
hGH-RIACT
Immunometric assay (mAb + mAb), radioactive
98/574
20 kD < 5%
Serum

DSL
DSL-10-1900 ACTIVE hGH ELISA
Immunometric assay, enzyme linked
80/505/88/624
Not provided
Serum
Provides standard concentrations for both calibrators

Full-size table

Abbreviations: pAb, polyclonal antiserum; mAb, monoclonal antibody.

View Within Article

It is important to keep in mind that many of the important studies on diagnosis and treatment of GH related diseases in the past have reported GH levels measured by competitive assays based on polyclonal antisera. The outcome of these studies of course still influences the current recommendations and guidelines for diagnosis and treatment of GH related diseases [13], [14], [15] and [16]. In addition, the actual values of GH concentrations mentioned in the older publications sometimes still influence clinical practice, although the assay methods underlying these numbers (or cut off values) are not used anymore [17]. It will be described below how changes in assay methods over time have altered the actual values of GH concentrations reported by the various assays, and why these differences create a continued problem for the clinical and scientific community.

2. Comparability of GH assay results

For many years external quality assessment schemes (EQAS) have documented large method- or laboratory dependent discrepancies between immunoassay results for several steroid- and peptide hormones. From this perspective, GH assays are only one unpleasant example of the difficulties in standardizing peptide hormone measurements [18] and [19]. The problem has been reported for GH assays from studies in several countries in the past [20], [21], [22] and [23]. The variability in concentrations reported for a single sample by different methods exceeds 100% in many cases. Obviously, this leads to problems when results from one study are compared to those from another study which used a different assay to measure GH concentrations. More relevant in clinical practice, this makes it impossible to compare GH assay results from one hospital to another when different assays and laboratories are used. Some studies directly compared results from different assays in the same clinical samples in one laboratory. In addition to confirming disagreement between results from different GH assays these studies also illustrated that the assay discrepancies affect the clinical interpretation of the results [24], [25] and [26].

3. Factors leading to poor comparability of GH assay results

Before discussing causes of method dependent discrepancies it is important to mention that in the case of GH the impact of problems in the preanalytical period on the results of laboratory measurements can be considered negligible. Although concentrations fluctuate considerably in the human body, GH exhibits a remarkable stability in vitro. It has been demonstrated that GH concentrations in serum samples remain stable for at least 24 h at room temperature and for even longer periods at 4 °C [27] and [28].

3.1. Molecular heterogeneity of the analyte

A major contributor to the heterogeneity of GH assay results is the fact that GH as secreted by the pituitary gland and circulating in the human body is a mixture of several molecular isoforms rather than a homogenous substance [29] and [30]. The most abundant isoform is a 22 kD GH molecule, followed by a smaller 20 kD molecule derived from alternative splicing. Hetero- and homodimers of the GH isoforms exist, and also multimers are present in human serum [31]. GH shares this feature of “molecular heterogeneity” with several other proteohormones such as hCG – and GH assays unfortunately share the poor comparability between methods with assays for other proteohormones [32] and [33]. Given the molecular heterogeneity of the analyte, measurement of such analytes by immunoassays inherently will lead to discrepant results depending on the antibodies used: Each immunoassay will pick up a selected spectrum of isoforms only – the epitopes of the respective antibodies used in the assays define which fraction of isoforms are translated into a signal in the respective assay. Because polyclonal antisera represent a mixture of different antibodies (each of which can potentially recognize different epitopes), the spectrum of isoforms measured by assays involving polyclonal antisera is most likely quite broad. In contrast, assays involving only monoclonal antibodies (which target only a very specific epitope) tend to recognize only a one or a few of the isoforms present in a sample. As a consequence, assays involving polyclonal antisera usually give higher results than those based on monoclonal assays. In addition, the heterogeneity of the analyte also serves as an explanation for why the agreement between GH assays was better when the less specific, polyclonal antisera were used [34] and [35], compared to recent years when monoclonal antibody based assays became predominant [21]. The higher specificity of the monoclonal antibodies led to more pronounced differences in the measurement results of different GH assays, and the overall between-method variability in the UK national EQAS worsened during the 90’s from about 17% to about 30%.

For most of the widely used GH assays information on the specific GH isoform measured by the respective assay is not provided by the manufacturer. One can assume that most of the assays recognize a certain spectrum of isoforms, and almost all will bind 22 kD GH because it is part of the antigen used by the manufacturers to generate the antibodies for the assays. Not relevant to clinical routine diagnostics, but helpful for research applications, are various GH assays designed to exclusively or preferentially measure individual GH isoforms. Such assays exist for the measurement of the 20 kD isoform [36] and [37], for placental GH or GH-V [38], for the whole spectrum of “non-22 kD” isoforms [39] and for the determination of the relative abundance of the 22 kD isoform [40].

A very recent difficulty in using GH measurements occurred when the GH receptor antagonist Pegvisomant was introduced in clinical practice for the treatment of acromegaly [41]. This drug is a modified GH molecule, leading to blockade of the GH receptor. The drug circulates at concentrations 100–1000 times higher than endogenous GH. Because of the molecular similarity to wild type GH and because of the high concentration, most commercially available GH assays cross-react with Pegvisomant [42]. Interestingly, the bias in GH assay results can be both, positive and negative, depending on the assay used: If both antibodies in a sandwich type GH assay cross-react with Pegvisomant, the results will be extremely high, whereas when only one of the antibodies cross-reacts, GH assay results can be falsely low. Only certain assays are available to specifically measure only endogenous GH in the presence of Pegvisomant [43], [44], [45] and [46], and the clinical relevance of GH determinations during Pegvisomant treatment is under investigation.

3.2. Reference preparations for GH assays

Another factor obviously influencing the comparability of assay results is the reference preparation or “standard” used to calibrate the assay. The concentration of an analyte in an immunoassay generally is determined by comparing the signal generated in the sample (with unknown concentration) to the signals generated in standard samples with known amounts of the analyte (standard curve). Therefore, immunoassay measurements are relative measurements in nature, and the composition and quality of the respective reference preparation has tremendous impact on the concentration reported by the assay. Historically, the first reference preparations for GH assays were pituitary extracts. Accordingly, the first international reference preparation (IRP) 66/217, introduced in 1969, and the following preparation 80/505, introduced in 1982, both contained a variety of GH isoforms, although some kind of purification was applied to increase the relative percentage of the 22 kD isoform. The “true” GH content in these two preparations was unknown and they were arbitrarily assigned concentrations of 2.0 and 2.6 U/mg, respectively. Subsequently, reference preparations of recombinant origin and consisting of the 22 kD isoform exclusively (IRP 88/624 and 98/574) became available. Although the recombinant origin and the high purity would allow expression of the GH content in mass units, the preparation IRP 88/624 was assigned to a biopotency of 3.0 U/mg to allow some kind of comparison to the previous pituitary extracts. The concomitant use of reference preparations of pituitary and recombinant origin in different GH assays clearly adds to the discrepancies between the assay results. In addition, the use of two units (mU/L and μg/L) and the adoption of a variety of conversion factors between the units further impaired the comparability of GH assay results [47] and [48]. Obviously, the change in the standard preparation has major influence on the absolute concentrations reported by different assays [23].

3.3. Impact of GHBP and other matrix components

In circulation, up to 50% of GH is complexed with a high affinity GH binding protein (GHBP) [49]. GHBP corresponds to the extracellular domain of the GH receptor, and its concentration varies with nutritional and metabolic conditions [50]. The presence of GHBP in serum samples becomes important for GH assays when epitopes of the respective antibodies used in a GH assay are no longer accessible due to steric hindrance by GHBP. Such a situation might lead to the underestimation of the GH concentration by the respective assay in samples containing GHBP at high concentrations. This problem was less pronounced in the past when assays with polyclonal antisera and long incubation times were used [51], but seems to be very relevant for newer assays using monoclonal antibodies with a defined epitope in conjunction with a very short incubation time. These assays have been shown to be susceptible to interference from GHBP, with a negative bias approaching 50% in some assays for GHBP concentrations still in the physiological range [52], [53] and [54].

Little is known about the potential impact of other matrix components on the results of GH assays. However, as some manufacturers, for example, do not recommend the use of EDTA plasma for use in GH assays because results tend to be higher than results from serum samples, one might speculate about factors other than GHBP influencing the assay results.

4. Clinical consequences of poor comparability of GH assay results

Poor comparability of GH assays has had significant clinical consequences, particularly for the diagnosis and monitoring of patients with GH deficiency and GH excess, acromegaly. The principal consequence is that no uniform GH criteria for these disorders can be developed so long as the assays remain heterogeneous.

In the case of acromegaly, determination of generalizable criteria for glucose-suppressed GH levels, obtained during an OGTT, to diagnose or determine cure of the disease has not been possible. With current sensitive and specific GH assays it is clear that the criteria in use in the past with polyclonal radio-immunoassays (RIA) of 2.0 μg/L for OGTT nadir or 2.5 μg/L for mean GH levels are no longer valid. With assays utilizing monoclonal antibodies it became evident that normal GH suppression after glucose is actually much <1 μg/L [12] and [55] and that levels should be <1 μg/L to exclude acromegaly or establish its remission [55] and [56]. However, exactly where below 1 μg/L this cut off should be cannot be uniformly agreed upon because the data vary depending upon the GH assay used [57], [58] and [59]. A number of studies support a cut off of 1 μg/L [59], [60] A.M. Arafat, M. Mohlig, M.O. Weickert, F.H. Perschel, J. Purschwitz, J. Spranger, C.J. Strasburger, C. Schofl and A.F. Pfeiffer, Growth hormone response during oral glucose tolerance test: the impact of assay method on the estimation of reference values in patients with acromegaly and in healthy controls, and the role of gender, age, and body mass index, J. Clin. Endocrinol. Metab. 93 (2008), pp. 1254–1262. View Record in Scopus | Cited By in Scopus (13)[60], [61] and [62] while others utilizing different assays suggest cut offs of 0.5 μg/L [60] and [63] or 0.25 μg/L [64]. An OGTT cut off of 0.3 μg/L has also been suggested with an assay that utilizes 2 monoclonal antibodies that are 22 K GH specific and standards that are calibrated to the recombinant human GH 22 K specific reference preparation 88/624 [54]. One source of variability in these cut offs is the GH standard utilized. The GH standards used in recent studies assessing normal and acromegaly OGTT criteria have varied from the WHO standard 80/505 which contains both 20 K and 22 K GH [12], [61] and [65] to polyclonal GH standards obtained from other sources such as the NIH and National Hormone and Pituitary Program [57] and [59] and to rhGH standards 88/624 [54] or 98/574 [60]. However, even when the same group of acromegaly samples were run in two different assays calibrated to the rhGH standard (98/574) significant differences were demonstrated [60]. In this study, the mean GH nadir in controlled acromegaly patients was 0.98 ± 0.26 μg/L with the Immulite 2000 assay vs. 0.5 ± 0.15 μg/L with the Nichols Advantage assay and in patients with active disease, these were 7.98 ± 1.7 μg/L and 4.5 ± 1.2 μg/L with these two assays, respectively. Nadir GH levels in healthy subjects are similarly variable making it difficult to establish normative data. When OGTT samples in healthy subjects were measured with three different assays calibrated to the rhGH standard (98/574) mean nadir GH concentrations varied from 0.13 ± 0.01 μg/L (range 0.05–0.99) with the Immulite 2000 assay to 0.06 ± 0.005 μg/L (range 0.02–0.5 μg/L) with the Nichols assay and to 0.015 ± 0.002 μg/L(range 0.00066–0.25 μg/L) with the Diagnostic Systems Laboratories Elisa assay. Differences in antibodies and other factors as described in this review likely play roles in determining the observed differences in GH data. Thus, it is clear that an optimal cut off applicable to all laboratories cannot be provided because of assay differences.

Variability between GH assays has led similarly to difficulty in standardizing those criteria for provocative testing of GH that can differentiate GH sufficiency from insufficiency. One study compared 699 peak GH levels obtained during stimulation testing of children undergoing evaluations for GH deficiency that were assayed in three different reference assays and local laboratories. The study found large differences between assays in mean GH levels, which ranged from 5.4 mU/l to 10.3 mU/l. Furthermore, diagnostic assignment varied in up to 27% of the children depending on the assay used [17]. Another study also found significant assay-dependent differences in peak stimulated GH in children with GH deficiency [66]. In this study and another, categorization of children into GH sufficient vs. deficient groups also varied markedly between assays [66] and [67]. Some authors have advocated for centralized reassessment of GH peak sera in reference centers in order to reduce variability in GH testing and utilization of these centralized results for treatment decisions [17]. Similar differences are likely to exist when measuring GH levels obtained during stimulation testing for the determination of GH deficiency in adults.

Therefore, it is clear that determination of optimal GH criteria for both acromegaly and GH deficiency has been hindered by the current heterogeneity of GH assays. A further consequence of the inability to derive uniform criteria is that published criteria developed with one assay are often adopted to interpret GH levels measured with another in the research setting, in guidelines publications and in clinical practice. In the latter setting, the use of inaccurate criteria to guide clinical decision-making could, in some cases, lead to errors in clinical care. The adoption of criteria developed with one assay to use with another may also have actually hindered the development of more uniformity because of a false sense of security that these criteria could be utilized more generally. Until such a time when more uniformity of GH assay methodology is adopted and/or appropriate normative data for each assay are developed, published diagnostic GH criteria for acromegaly or GH deficiency can only serve as a general guideline. Some steps could improve more widespread use of published criteria in the meantime as outlined below.

5. Points for discussion

There is increasing awareness of the problem of GH assay variability [68] and [69]. Recently an international collaborative started to discuss options to improve the situation [70] and [71]. and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has put the issue of GH assays on the agenda by implementing a Working Group on GH assay standardization [72] and [73]. Experience with attempts to standardize other hormone assays has demonstrated that standardization of immunoassays requires compromises – no one approach is likely to adequately address all the issues related to the problem. The quality required for a particular assay has to consider clinical needs and theoretical and practical limitations [74]. Future attempts to standardize or harmonize GH assays should consider the following issues (key points summarized in Table 2):


Table 2.

Suggested points for the discussion of future attempts to standardize GH assays.

Issue
Points to discuss

Molecular heterogeneity of GH
Which isoforms are important to be measured?

Is a mathematical conversion of concentration values obtained by different assays possible and reliable?

Assay calibration
How can the use of a single calibrant (recombinant hGH 98/574) be achieved worldwide?

Which factors have to be taken into account when preparing standards for assays?

What is a “commutable” standard preparation?

Assay validation and performance control
What recommendations can be made for procedures to investigate isoform crossreactivity and potential impact of GHBP?

Is there a need to eliminate GHBP interference?

Is it required to determine the respective epitopes of all antibodies used in GH assays?

Clinical interpretation and cut off values
Are “assay specific cut off values” an attainable goal?

What could be done to establish cut off values applicable for a broad spectrum of assays?

Which physiological factors have to be taken into account for the establishment of cut off values for dynamic tests?

Full-size table

View Within Article

5.1. Issues related to the molecular heterogeneity of GH
5.1.1. Which GH isoform should be measured?

It is a matter of debate whether a more specific or a more permissive recognition of GH isoforms is preferable from a clinical point of view. It has been shown convincingly that different isoforms are biologically active [75], and therefore one is potentially missing information with assays that measure only one isoform [18]. However, one might also argue that even up to today no specific clinical condition has been found where the response to dynamic tests (stimulation or suppression) differed with respect to the different molecular isoforms. As 22 kD GH is by far the most abundant isoform, it might be sufficient to have a specific measurement of this isoform only. Whatever the final recommendation with respect to the preferred analyte for GH assays – it is very important for each GH assay’s proper interpretation that each assay manufacturer provide specific information on the isoform measured by their respective GH assay.

5.1.2. Is it possible to “translate” GH assay results from one assay to another?

The discrepancy between the concentrations obtained from measurement of GH by two different immunoassays depends on factors related to the respective assays (antibody specificity, assay design, etc.), but also on factors related to the individual sample analysed, mainly the relative abundance of the GH isoforms present in the respective sample. Therefore, it is impossible to make results from different immunoassays comparable by simply applying a linear “conversion factor”. This is especially important to keep in mind when considering assays employing monoclonal antibodies – they are particularly sensitive to the isoform composition of each sample. Furthermore, the respective impact of GHBPs present in the individual samples will affect the “commutability” of assay results. From this point of view it is unlikely that published recommendations for cut off values based on older, polyclonal GH assays can be “translated” into cut offs valid for the newer, automated immunoassay systems. An experimental approach to reduce discrepancies between GH assay results has been reported recently [76]: So-called “harmonization samples” (representing “average patient samples”) are distributed among laboratories, measured with the local assays and used to correct the respective GH assay results for all other samples measured in the lab. The authors of that study report a reduction in between-laboratory variability for GH assay results from 15% to <7%. The concept is interesting, but also has its problems: First, it is unlikely that an “average patient sample” is able to adequately represent the potential interference of isoforms, GHBP and other factors. Furthermore, the study had been conducted with a rather small number of laboratories, and it might be difficult to apply this concept to a larger international setting because the availability of sufficient amounts of adequate harmonization samples is a prerequisite.

5.2. Issues related to assay calibration
5.2.1. Which calibrator should be used for GH assays?

The international collaborative on GH assay standardization has recommended the sole use of the recombinant IRP of 22 kD GH 98/574, and that GH assay results be expressed in mass units (μg/L) of this preparation. Although there are still some assays on the market that are calibrated against the older pituitary extract preparations, there is a tendency towards standardization on this point. The study by Tanaka et al. [23] has clearly shown the potential benefit of such harmonization of the assay calibrant. Furthermore, only reference materials of recombinant origin and high purity could allow traceability of GH assay results [77]. Meanwhile, some important journals in the field have decided to only publish papers that include GH data that are expressed in mass units of the most recent International Standard 98/574 [70] and [71]. However, this approach is problematic as several manufacturers – including the market leader – have yet to implement the change in the calibrator in all countries. Thus, GH assays from the same manufacturer have been – and still are – available with different calibrators in different European countries. If and when the corresponding change will be implemented for assays available in the US is still unclear. As a result, the journal’s requirement at this time that GH values be expressed only in mass units of the IRP 98/574 is not tenable. However, it is clear that researchers must be extremely careful in reporting the correct calibration for the GH assays they used to measure their samples.

Clearly, several problems with GH assays cannot be solved solely by using a single calibrator for all assays. Furthermore, it is important to keep in mind that the potency of standard preparations used for GH assays also can be affected by the way the reference preparations (e.g. 98/574) are treated to obtain the calibration solution used for the respective assay. E.g. the matrix of the assay specific calibrators is different between assays from different manufacturers. Commutability of immunoassay results is a complex task [78]. It remains to be investigated to what degree the “standardization of the standard” alone will lead to better comparability of GH assay results [79].

5.3. Issues related to assay validation and performance control
5.3.1. What information must be given for GH assays with respect to specificity and interference?

Precise characterization of each GH assay with respect to both the GH isoform spectrum recognized, and to potential interference from GHBP is desirable. However, conducting the necessary experiments is challenging because of the limited availability of the substances required. Although recombinant 22 kD GH is easily available, access to the 20 kD isoform is more difficult, and general availability of homo- and heterodimers of isoforms might remain impossible. For GHBP, some recombinant preparations are commercially available, but these preparations are produced in non-mammalian cell culture systems. As a consequence, the recombinant GHBP preparations contain non-glycosylated GHBP only, whereas endogenous GHBP is glycosylated. Whether or not glycosylation status affects the degree of potential interference of GHBP in immunoassays is unknown. The scientific community should provide clear guidelines on reagents and procedures to be used in GH assay validation.

5.4. Issues related to the clinical interpretation of GH assay data
5.4.1. What are quality criteria for establishing cut off values?

Given the heterogeneity of GH assay results, most guidelines emphasize the need for “method specific cut off values” and point out the problem of assay variability [13], [14], [16] and [80]. Such an approach may be ideal as some aspects of each GH assay will never be completely universally comparable. However, for most of the assays currently in use in large clinical laboratories world wide there are no published studies or reference data available. Establishing such data requires resources and sometimes is very difficult or even impossible for ethical reasons – e.g. in children. In addition, normative data for GH will need to individualized for age, gender and BMI as these factors are important for determining GH levels in OGTT testing as well as stimulation testing for GH. Laboratories working in a highly competitive economic environment very likely are unable to produce such reference values for any new GH assay introduced. One strategy would be to develop reference populations from a multi-center effort that could then be shared across laboratories and assayed with multiple assays, but this too would require considerable resources.

5.4.2. Given the inherent differences between concentrations determined by different immunoassays – what can be done to improve reliability of applying guidelines and recommendations?

If assay specific normative data cannot be established then certain minimal steps may help establish some comparability and allow for applicability of cut offs with one assay to the other. The first and most straightforward step is universal adoption of the rhGH standard as described above. A second step could be to advocate for transparency on the part of assay manufacturers about the characteristics on their assay, in particular the specificity of the antibodies and the potential interferences as outlined throughout this manuscript. Collaborative efforts between researchers and industry to establish reference criteria for different categories of GH assays along with transparency of the factors described above could help create some published criteria that are more generalizable.

References

[1] C.A. Gemzell, F. Heijkenskjold and L. Strom, A method for demonstrating growth hormone activity in human plasma, J. Clin. Endocrinol. Metab. 15 (1955), pp. 537–546. View Record in Scopus | Cited By in Scopus (2)

[2] A. Segaloff, E.L. Komrad, A. Flores, A. Segaloff and M. Hardesty, The growth hormone content of human plasma, Endocrinology 57 (1955), pp. 527–530. View Record in Scopus | Cited By in Scopus (2)

[3] M.T. Dattani, P.C. Hindmarsh, C.G. Brook, I.C. Robinson, T. Weir and N.J. Marshall, Enhancement of growth hormone bioactivity by zinc in the eluted stain assay system, Endocrinology 133 (1993), pp. 2803–2808. View Record in Scopus | Cited By in Scopus (22)

[4] M.A. Lesniak, P. Gorden, J. Roth and J.R. Gavin 3rd, Binding of 125I-human growth hormone to specific receptors in human cultured lymphocytes. Characterization of the interaction and a sensitive radioreceptor assay, J. Biol. Chem. 249 (1974), pp. 1661–1667. View Record in Scopus | Cited By in Scopus (43)

[5] R.S. Yalow and S.A. Berson, Assay of plasma insulin in human subjects by immunological methods, Nature 184 (Suppl. 21) (1959), pp. 1648–1649.

[6] R.M. Ehrlich and P.J. Randle, Immunoassay of growth hormone in human serum, Lancet 2 (1961), pp. 230–233. Abstract | Article | PDF (644 K) | View Record in Scopus | Cited By in Scopus (2)

[7] D.S. Schalch and M.L. Parker, A Sensitive double antibody immunoassay for human growth hormone in plasma, Nature 203 (1964), pp. 1141–1142.

[8] H.G. Morris, Y. Arai, C.J. Hlad Jr., R. Tompkins and H. Elrick, Rapid quantitative immunologic assay for human growth hormone, J. Clin. Endocrinol. Metab. 24 (1964), pp. 417–424.

[9] H. Orskov, H.G. Thomsen and H. Yde, Wick chromatography for rapid and reliable immunoassay of insulin, glucagon and growth hormone, Nature 219 (1968), pp. 193–195. View Record in Scopus | Cited By in Scopus (114)

[10] B.K. van Weemen, The rise of EIA/ELISA, Clin. Chem. 51 (2005), p. 2226. View Record in Scopus | Cited By in Scopus (3)

[11] A.H. Wu, A selected history and future of immunoassay development and applications in clinical chemistry, Clin. Chim. Acta 369 (2006), pp. 119–124. Abstract | Article | PDF (519 K) | View Record in Scopus | Cited By in Scopus (14)

[12] I.M. Chapman, M.L. Hartman, M. Straume, M.L. Johnson, J.D. Veldhuis and M.O. Thorner, Enhanced sensitivity growth hormone (GH) chemiluminescence assay reveals lower postglucose nadir GH concentrations in men than women, J. Clin. Endocrinol. Metab. 78 (1994), pp. 1312–1319. View Record in Scopus | Cited By in Scopus (135)

[13] Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the growth hormone research society workshop on adult growth hormone deficiency, J. Clin. Endocrinol. Metab. 83 (1998) 379–381.

[14] Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH research society, J. Clin. Endocrinol. Metab. 85 (2000) 3990–3993.

[15] A. Giustina, A. Barkan, F.F. Casanueva, F. Cavagnini, L. Frohman, K. Ho, J. Veldhuis, J. Wass, K. Von Werder and S. Melmed, Criteria for cure of acromegaly: a consensus statement, J. Clin. Endocrinol. Metab. 85 (2000), pp. 526–529. View Record in Scopus | Cited By in Scopus (514)

[16] S. Melmed, F. Casanueva, F. Cavagnini, P. Chanson, L.A. Frohman, R. Gaillard, E. Ghigo, K. Ho, P. Jaquet, D. Kleinberg, S. Lamberts, E. Laws, G. Lombardi, M.C. Sheppard, M. Thorner, M.L. Vance, J.A. Wass and A. Giustina, Consensus statement: medical management of acromegaly, Eur. J. Endocrinol. 153 (2005), pp. 737–740. View Record in Scopus | Cited By in Scopus (87)

[17] B.P. Hauffa, N. Lehmann, M. Bettendorf, O. Mehls, H.G. Dorr, C.J. Partsch, H.P. Schwarz, N. Stahnke, H. Steinkamp, E. Said, S. Sander and M.B. Ranke, Central reassessment of GH concentrations measured at local treatment centers in children with impaired growth: consequences for patient management, Eur. J. Endocrinol. 150 (2004), pp. 291–297. View Record in Scopus | Cited By in Scopus (26)

[18] V. Popii and G. Baumann, Laboratory measurement of growth hormone, Clin. Chim. Acta 350 (2004), pp. 1–16. Abstract | Article | PDF (193 K) | View Record in Scopus | Cited By in Scopus (34)

[19] C.J. Strasburger and M. Bidlingmaier, How robust are laboratory measures of growth hormone status?, Horm. Res. 64 (Suppl. 2) (2008), pp. 1–5. View Record in Scopus | Cited By in Scopus (0)

[20] F. Bidlingmaier, W.J. Geilenkeuser, R. Kruse and G. Rohle, Our experience with quality control in current growth hormone assays, Horm. Res. 36 (Suppl. 1) (1991), pp. 1–4. View Record in Scopus | Cited By in Scopus (8)

[21] J. Seth, A. Ellis and R. Al-Sadie, Serum growth hormone measurements in clinical practice: an audit of performance from the UK National External Quality Assessment scheme, Horm. Res. 51 (1999), pp. 13–19. View Record in Scopus | Cited By in Scopus (29)

[22] P. Morsky, U. Tiikkainen, A. Ruokonen and H. Markkanen, Problematic determination of serum growth hormone: experience from external quality assurance surveys 1998–2003, Scand. J. Clin. Lab. Invest. 65 (2005), pp. 377–386. View Record in Scopus | Cited By in Scopus (7)

[23] T. Tanaka, K. Tachibana, A. Shimatsu, N. Katsumata, T. Tsushima, N. Hizuka, K. Fujieda, S. Yokoya and M. Irie, A nationwide attempt to standardize growth hormone assays, Horm. Res. 64 (Suppl. 2) (2005).

[24] A.C. Celniker, A.B. Chen, R.M. Wert Jr. and B.M. Sherman, Variability in the quantitation of circulating growth hormone using commercial immunoassays, J. Clin. Endocrinol. Metab. 68 (1989), pp. 469–476. View Record in Scopus | Cited By in Scopus (93)

[25] M.L. Granada, A. Sanmarti, A. Lucas, I. Salinas, A. Carrascosa and M. Foz, Assay-dependent results of immunoassayable spontaneous 24-hour growth hormone secretion in short children, Acta Paediatr. Scand. (Suppl. 370) (1990), pp. 63–70 (discussion 71). View Record in Scopus | Cited By in Scopus (40)

[26] H. Markkanen, T. Pekkarinen, M.J. Valimaki, H. Alfthan, R. Kauppinen-Makelin, T. Sane and U.H. Stenman, Effect of sex and assay method on serum concentrations of growth hormone in patients with acromegaly and in healthy controls, Clin. Chem. 52 (2006), pp. 468–473. View Record in Scopus | Cited By in Scopus (15)

[27] R.L. Derr, S.J. Cameron and S.H. Golden, Pre-analytic considerations for the proper assessment of hormones of the hypothalamic–pituitary axis in epidemiological research, Eur. J. Epidemiol. 21 (2006), pp. 217–226. View Record in Scopus | Cited By in Scopus (4)

[28] M.J. Evans, J.H. Livesey, M.J. Ellis and T.G. Yandle, Effect of anticoagulants and storage temperatures on stability of plasma and serum hormones, Clin. Biochem. 34 (2001), pp. 107–112. Abstract | Article | PDF (70 K) | View Record in Scopus | Cited By in Scopus (70)

[29] G. Baumann, Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins, Endocr. Rev. 12 (1991), pp. 424–449. View Record in Scopus | Cited By in Scopus (247)

[30] G. Baumann, Growth hormone heterogeneity in human pituitary and plasma, Horm. Res. 51 (1999), pp. 2–6. View Record in Scopus | Cited By in Scopus (56)

[31] G. Baumann, M.W. Stolar and T.A. Buchanan, The metabolic clearance, distribution, and degradation of dimeric and monomeric growth hormone (GH): implications for the pattern of circulating GH forms, Endocrinology 119 (1986), pp. 1497–1501. View Record in Scopus | Cited By in Scopus (23)

[32] C.M. Sturgeon, P. Berger, J.M. Bidart, S. Birken, C. Burns, R.J. Norman and U.H. Stenman, Differences in recognition of the 1st WHO international reference reagents for hCG-related isoforms by diagnostic immunoassays for human chorionic gonadotropin, Clin. Chem. 55 (2009), pp. 1484–1491. View Record in Scopus | Cited By in Scopus (5)

[33] C.M. Sturgeon and A.R. Ellis, Standardization of FSH, LH and hCG – current position and future prospects, Mol. Cell. Endocrinol. 260–262 (2007), pp. 301–309. Abstract | Article | PDF (276 K) | View Record in Scopus | Cited By in Scopus (11)

[34] P. Chatelain, B. Bouillat, R. Cohen, G. Sassolas, J.C. Souberbielle, A. Ruitton, M.O. Joly and J.C. Job, Assay of growth hormone levels in human plasma using commercial kits: analysis of some factors influencing the results, Acta Paediatr. Scand. (Suppl. 370) (1990), pp. 56–61 (discussion 62). View Record in Scopus | Cited By in Scopus (30)

[35] E.O. Reiter, A.H. Morris, M.H. MacGillivray and D. Weber, Variable estimates of serum growth hormone concentrations by different radioassay systems, J. Clin. Endocrinol. Metab. 66 (1988), pp. 68–71. View Record in Scopus | Cited By in Scopus (44)

[36] T. Tsushima, Y. Katoh, Y. Miyachi, K. Chihara, A. Teramoto, M. Irie and Y. Hashimoto, Serum concentration of 20K human growth hormone (20K hGH) measured by a specific enzyme-linked immunosorbent assay. Study group of 20K hGH, J. Clin. Endocrinol. Metab. 84 (1999), pp. 317–322 ISSN: 0021-972x. View Record in Scopus | Cited By in Scopus (46)

[37] K.C. Leung, C. Howe, L.Y. Gui, G. Trout, J.D. Veldhuis and K.K. Ho, Physiological and pharmacological regulation of 20-kDa growth hormone, Am. J. Physiol. Endocrinol. Metab. 283 (2002), pp. E836–E843. View Record in Scopus | Cited By in Scopus (25)

[38] Z. Wu, M. Bidlingmaier, R. Dall and C.J. Strasburger, Detection of doping with human growth hormone, Lancet 353 (1999), p. 895. Abstract | Article | PDF (43 K) | View Record in Scopus | Cited By in Scopus (93)

[39] C.L. Boguszewski, M.C. Boguszewski, F. de Zegher, B. Carlsson and L.M. Carlsson, Growth hormone isoforms in newborns and postpartum women, Eur. J. Endocrinol. 142 (2000), pp. 353–358. View Record in Scopus | Cited By in Scopus (9)

[40] M. Bidlingmaier, J. Suhr, A. Ernst, Z. Wu, A. Keller, C.J. Strasburger and A. Bergmann, High-sensitivity chemiluminescence immunoassays for detection of growth hormone doping in sports, Clin. Chem. 55 (2009), pp. 445–453. View Record in Scopus | Cited By in Scopus (9)

[41] P.J. Trainer, W.M. Drake, L. Katznelson, P.U. Freda, V. Herman-Bonert, A.J. van der Lely, E.V. Dimaraki, P.M. Stewart, K.E. Friend, M.L. Vance, G.M. Besser, J.A. Scarlett, M.O. Thorner, C. Parkinson, A. Klibanski, J.S. Powell, A.L. Barkan, M.C. Sheppard, M. Malsonado, D.R. Rose, D.R. Clemmons, G. Johannsson, B.A. Bengtsson, S. Stavrou, D.L. Kleinberg, D.M. Cook, L.S. Phillips, M. Bidlingmaier, C.J. Strasburger, S. Hackett, K. Zib, W.F. Bennett and R.J. Davis, Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant, N. Engl. J. Med. 342 (2000), pp. 1171–1177. View Record in Scopus | Cited By in Scopus (317)

[42] A.N. Paisley, K. Hayden, A. Ellis, J. Anderson, G. Wieringa and P.J. Trainer, Pegvisomant interference in GH assays results in underestimation of GH levels, Eur. J. Endocrinol. 156 (2007), pp. 315–319. View Record in Scopus | Cited By in Scopus (11)

[43] M.O. Thorner, C.J. Strasburger, Z. Wu, M. Straume, M. Bidlingmaier, S.S. Pezzoli, K. Zib, J.C. Scarlett and W.F. Bennett, Growth hormone (GH) receptor blockade with a PEG-modified GH (B2036-PEG) lowers serum insulin-like growth factor-I but does not acutely stimulate serum GH, J. Clin. Endocrinol. Metab. 84 (1999), pp. 2098–2103. View Record in Scopus | Cited By in Scopus (75)

[44] J.D. Veldhuis, M. Bidlingmaier, S.M. Anderson, Z. Wu and C.J. Strasburger, Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy women and men, J. Clin. Endocrinol. Metab. 86 (2001), pp. 3304–3310. View Record in Scopus | Cited By in Scopus (52)

[45] A. Colao, R. Pivonello, R.S. Auriemma, M.C. De Martino, M. Bidlingmaier, F. Briganti, F. Tortora, P. Burman, I.A. Kourides, C.J. Strasburger and G. Lombardi, Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance, Eur. J. Endocrinol. 154 (2006), pp. 467–477. View Record in Scopus | Cited By in Scopus (48)

[46] S.R. Brian, M. Bidlingmaier, M.P. Wajnrajch, S.A. Weinzimer and S.E. Inzucchi, Treatment of acromegaly with pegvisomant during pregnancy: maternal and fetal effects, J. Clin. Endocrinol. Metab. 92 (2007), pp. 3374–3377. View Record in Scopus | Cited By in Scopus (9)

[47] A. Pokrajac, G. Wark, A.R. Ellis, J. Wear, G.E. Wieringa and P.J. Trainer, Variation in GH and IGF-I assays limits the applicability of international consensus criteria to local practice, Clin. Endocrinol. 67 (2007), pp. 65–70. View Record in Scopus | Cited By in Scopus (26)

[48] P.J. Trainer, J. Barth, C. Sturgeon and G. Wieringaon, Consensus statement on the standardisation of GH assays, Eur. J. Endocrinol. 155 (2006), pp. 1–2. View Record in Scopus | Cited By in Scopus (0)

[49] G. Baumann, Growth hormone binding protein 2001, J. Pediatr. Endocrinol. Metab. 14 (2001), pp. 355–375. View Record in Scopus | Cited By in Scopus (75)

[50] T. Amit, M.B. Youdim and Z. Hochberg, Clinical review 112: does serum growth hormone (GH) binding protein reflect human GH receptor function?, J. Clin. Endocrinol. Metab. 85 (2000), pp. 927–932. View Record in Scopus | Cited By in Scopus (49)

[51] T. Jan, M.A. Shaw and G. Baumann, Effects of growth hormone-binding proteins on serum growth hormone measurements, J. Clin. Endocrinol. Metab. 72 (1991), pp. 387–391. View Record in Scopus | Cited By in Scopus (26)

[52] L. Ebdrup, S. Fisker, H.H. Sorensen, M.B. Ranke and H. Orskov, Variety in growth hormone determinations due to use of different immunoassays and to the interference of growth hormone-binding protein, Horm. Res. 51 (1999), pp. 20–26. View Record in Scopus | Cited By in Scopus (31)

[53] C. Jansson, C. Boguszewski, S. Rosberg, L. Carlsson and K. Albertsson-Wikland, Growth hormone (GH) assays: influence of standard preparations, GH isoforms, assay characteristics, and GH-binding protein, Clin. Chem. 43 (1997), pp. 950–956. View Record in Scopus | Cited By in Scopus (55)

[54] T.K. Hansen, S. Fisker, B. Hansen, H.H. Sorensen, J.S. Christiansen, J.O. Jorgensen and H. Orskov, Impact of GHBP interference on estimates of GH and GH pharmacokinetics, Clin. Endocrinol. 57 (2002), pp. 779–786. View Record in Scopus | Cited By in Scopus (18)

[55] P.U. Freda, K.D. Post, J.S. Powell and S.L. Wardlaw, Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly, J. Clin. Endocrinol. Metab. 83 (1998), pp. 3808–3816. View Record in Scopus | Cited By in Scopus (127)

[56] P.U. Freda, Pitfalls in the biochemical assessment of acromegaly, Pituitary 6 (2003), pp. 135–140. View Record in Scopus | Cited By in Scopus (12)

[57] A.C. Costa, A. Rossi, C.E. Martinelli Jr., H.R. Machado and A.C. Moreira, Assessment of disease activity in treated acromegalic patients using a sensitive GH Assay: should we achieve strict normal GH levels for a biochemical cure?, J. Clin. Endocrinol. Metab. 87 (2002), pp. 3142–3147. View Record in Scopus | Cited By in Scopus (41)

[58] P.U. Freda, Current concepts in the biochemical assessment of the patient with acromegaly, Growth Horm. IGF Res. 13 (2003), pp. 171–184. Abstract | Article | PDF (176 K) | View Record in Scopus | Cited By in Scopus (36)

[59] N. Hattori, A. Shimatsu, Y. Kato, H. Koshiyama, Y. Ishikawa, H. Assadian, T. Tanoh, M. Nagao and H. Imura, Growth hormone responses to oral glucose loading measured by highly sensitive enzyme immunoassay in normal subjects and patients with glucose intolerance and acromegaly, J. Clin. Endocrinol. Metab. 70 (1990), pp. 771–776. View Record in Scopus | Cited By in Scopus (30)

[60] A.M. Arafat, M. Mohlig, M.O. Weickert, F.H. Perschel, J. Purschwitz, J. Spranger, C.J. Strasburger, C. Schofl and A.F. Pfeiffer, Growth hormone response during oral glucose tolerance test: the impact of assay method on the estimation of reference values in patients with acromegaly and in healthy controls, and the role of gender, age, and body mass index, J. Clin. Endocrinol. Metab. 93 (2008), pp. 1254–1262. View Record in Scopus | Cited By in Scopus (13)

[61] L. De Marinis, A. Mancini, A. Bianchi, R. Gentilella, D. Valle, A. Giampietro, P. Zuppi, C. Anile, G. Maira and A. Giustina, Preoperative growth hormone response to thyrotropin-releasing hormone and oral glucose tolerance test in acromegaly: a retrospective evaluation of 50 patients, Metabolism 51 (2002), pp. 616–621. Abstract | PDF (90 K) | View Record in Scopus | Cited By in Scopus (12)

[62] M. Mercado, A.L. Espinosa de los Monteros, E. Sosa, S. Cheng, V. Mendoza, I. Hernandez, C. Sandoval, G. Guinto and M. Molina, Clinical-biochemical correlations in acromegaly at diagnosis and the real prevalence of biochemically discordant disease, Horm. Res. 62 (2004), pp. 293–299. View Record in Scopus | Cited By in Scopus (6)

[63] R.A. Feelders, M. Bidlingmaier, C.J. Strasburger, J.A. Janssen, P. Uitterlinden, L.J. Hofland, S.W. Lamberts, A.J. van der Lely and W.W. de Herder, Postoperative evaluation of patients with acromegaly: clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor I, acid-labile subunit, and growth hormone-binding protein levels, J. Clin. Endocrinol. Metab. 90 (2005), pp. 6480–6489. View Record in Scopus | Cited By in Scopus (18)

[64] O. Serri, C. Beauregard and J. Hardy, Long-term biochemical status and disease-related morbidity in 53 postoperative patients with acromegaly, J. Clin. Endocrinol. Metab. 89 (2004), pp. 658–661. View Record in Scopus | Cited By in Scopus (38)

[65] E.V. Dimaraki, C.A. Jaffe, R. DeMott-Friberg, W.F. Chandler and A.L. Barkan, Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up, J. Clin. Endocrinol. Metab. 87 (2002), pp. 3537–3542. View Record in Scopus | Cited By in Scopus (98)

[66] Y. Rakover, I. Lavi, R. Masalah, T. Issam, E. Weiner and I. Ben-Shlomo, Comparison between four immunoassays for growth hormone (GH) measurement as guides to clinical decisions following GH provocative tests, J. Pediatr. Endocrinol. Metab. 13 (2000), pp. 637–643 (In Process Citation). View Record in Scopus | Cited By in Scopus (10)

[67] S. Amed, E. Delvin and J. Hamilton, Variation in growth hormone immunoassays in clinical practice in Canada, Horm. Res. 69 (2008), pp. 290–294. View Record in Scopus | Cited By in Scopus (4)

[68] A. Juul, S. Bernasconi, P.E. Clayton, W. Kiess and S. DeMuinck-Keizer Schrama, European audit of current practice in diagnosis and treatment of childhood growth hormone deficiency, Horm. Res. 58 (2002), pp. 233–241. View Record in Scopus | Cited By in Scopus (23)

[69] G.E. Wieringa, J.H. Barth and P.J. Trainer, Growth hormone assay standardization: a biased view?, Clin. Endocrinol. 60 (2004), pp. 538–539. View Record in Scopus | Cited By in Scopus (19)

[70] P.J. Trainer, J. Barth, C. Sturgeon and G. Wieringa, Consensus statement on the standardisation of GH assays, Eur. J. Endocrinol. 155 (2006), pp. 1–2. View Record in Scopus | Cited By in Scopus (30)

[71] M.C. Sheppard, Growth hormone assay standardization: an important clinical advance, Clin. Endocrinol. 66 (2007), pp. 157–161. View Record in Scopus | Cited By in Scopus (12)

[72] M. Bidlingmaier and C.J. Strasburger, Growth hormone assays: current methodologies and their limitations, Pituitary 10 (2007), pp. 115–119. View Record in Scopus | Cited By in Scopus (17)

[73] M. Bidlingmaier and C.J. Strasburger, What endocrinologists should know about growth hormone measurements, Endocrinol. Metab. Clin. North Am. 36 (2007), pp. 101–108. Abstract | Article | PDF (118 K) | View Record in Scopus | Cited By in Scopus (4)

[74] U.H. Stenman, Immunoassay standardization: is it possible, who is responsible, who is capable?, Clin. Chem. 47 (2001), pp. 815–820.

[75] M. Hayakawa, Y. Shimazaki, T. Tsushima, Y. Kato, K. Takano, K. Chihara, A. Shimatsu and M. Irie, Metabolic effects of 20-kilodalton human growth hormone (20K-hGH) for adults with growth hormone deficiency: results of an exploratory uncontrolled multicenter clinical trial of 20K-hGH, J. Clin. Endocrinol. Metab. 89 (2004), pp. 1562–1571. View Record in Scopus | Cited By in Scopus (10)

[76] H.A. Ross, Reporting growth hormone assay results in terms of one consensus recombinant standard preparation offers less than optimal reduction of between-method variation, Clin. Chem. Lab. Med. 46 (2008), pp. 1334–1335. View Record in Scopus | Cited By in Scopus (3)

[77] R.M. Lequin, Standardization: comparability and traceability of laboratory results, Clin. Chem. 48 (2002), pp. 391–393. View Record in Scopus | Cited By in Scopus (4)

[78] W.G. Miller, G.L. Myers and R. Rej, Why commutability matters, Clin. Chem. 52 (2006), pp. 553–554. View Record in Scopus | Cited By in Scopus (20)

[79] M. Bidlingmaier, Problems with GH assays and strategies toward standardization, Eur. J. Endocrinol. 159 (Suppl. 1) (2008), pp. S41–S44. View Record in Scopus | Cited By in Scopus (2)

[80] M.E. Molitch, D.R. Clemmons, S. Malozowski, G.R. Merriam, S.M. Shalet, M.L. Vance and P.A. Stephens, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline, J. Clin. Endocrinol. Metab. 91 (2006), pp. 1621–1634. View Record in Scopus | Cited By in Scopus (110)

[81] K. Iwahara, C. Tanabe and M. Maekawa, Comparison of access ultrasensitive human growth hormone assay to monoclonal antibody-based immunoradiometric assay, Clin. Chim. Acta 376 (2007), pp. 248–249. Abstract | Article | PDF (145 K) | View Record in Scopus | Cited By in Scopus (1)

Corresponding Author Contact InformationCorresponding author. Address: Endocrine Research Laboratories, Medizinische Klinik – Innenstadt, Ludwig-Maximilians University, Ziemssenstr. 1, Munich, Germany. Tel.: +49 8951602277.
1 MB has received lecture fees from DiaSorin, consultancy fees from IDS and research support from IDS, Diasorin, Siemens and DSL.


Growth Hormone & IGF Research
Volume 20, Issue 1, February 2010, Pages 19-25

From http://www.sciencedirect.com