Effect of Pegvisomant on GH/IGF-I Relationship in GHD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00468624
Recruitment Status : Terminated (recruitment completed)
First Posted : May 3, 2007
Last Update Posted : May 3, 2007
Information provided by:
The Christie NHS Foundation Trust

Brief Summary:
Approximately 50% of middle-aged patients with severe AGHD have a normal age-related serum IGF-I. It remains unclear if in these individuals serum IGF-I is GH dependent or independent. This study compared the relationship between GH and serum IGF-I in two cohorts of male patients with severe AGHD; one with normal and the other with subnormal age-related serum IGF-I values. The GH receptor antagonist - pegvisomant was be used to specifically inhibit GH action and the changes in markers of the GH axis, such as serum IGF-I, IGFBP-3, GH and GHBP were measured.

Condition or disease Intervention/treatment Phase
Severe Adult Growth Hormone Deficiency Drug: pegvisomant/placebo loading dose 80mg sc, thereafter 20mg daily for 2 weeks Procedure: GH sampling - every 20 min over 24 hours after each limb (pegvisomant/placebo) Procedure: blood sampling before and after pegvisomant/placebo Procedure: arginine stimulation test after each limb Not Applicable

Detailed Description:

There is an increasing reliance on serum insulin-like factor-I (IGF-I) in the management of disturbances of the growth hormone (GH) axis. IGF-I is predominantly, but not exclusively, regulated by GH secreted from the pituitary, with the majority of circulating IGF-I being hepatic in origin.

In parallel with the age-related decline in GH secretion, circulating levels of IGF-I fall with age (1). For a given GH level women have lower serum IGF-I levels than men, indicative of a relative GH resistance (1,2). Nutrition-related factors are known to affect GH, IGF-I and their relationship. Obesity is associated with low GH production, but increased GH sensitivity resulting in relatively high IGF-I for given GH (3-6). Deprivation of important nutrients during fasting is known to stimulate GH, whilst reducing IGF-I (7-9). In vitro studies demonstrated complex role of insulin in IGF-I generation. Insulin stimulates hepatic IGF-I production directly by increasing IGF-I mRNA synthesis and indirectly by enhancing the effect of GH (10,11). By decreasing insulin-like growth factor 1 and 2 (IGFBP1-2), insulin may also affect bioavailability of IGF-I (12-13).

In acromegaly, IGF-I is an important marker for diagnosis and monitoring of disease activity. If patients are treated with a GH receptor antagonist, IGF-I becomes the only useful biochemical marker for monitoring disease activity.

GH deficiency in adults is associated with increased morbidity (14-16). In patients with pituitary disease there has been great progress in the recognition and treatment of this disorder. There is increasing awareness of GH deficiency, not only as a complication of the long-recognised causes of hypopituitarism, but also in the setting of traumatic brain injury and subarachnoid haemorrhage (17). The phenotype of severe adult GHD has been described but many of the features lack specificity and biochemical confirmation of the diagnosis is necessary. The Port Stevens consensus on severe adult GHD relies on the measurement of stimulated GH secretion for confirmation of the diagnosis with a peak GH of <3 µg/L, in one or two stimulation tests, depending on the number of other pituitary hormone deficiencies (18) GH replacement therapy relies on measurement of serum IGF-I for dose titration, with the biochemical goal being of placing circulating IGF-I within age- and gender-related reference range, preferably between 0 and +1 SDS (19). The Port Stephens consensus recognises the apparent paradox that approximately 50% of middle-aged patients diagnosed with severe GHD by a peak stimulated GH levels of <3 µg/L have a pre-treatment IGF-I within the reference range. In untreated severe GHD of adult onset and predominately in men, serum IGF-I may even be in the upper half of reference range. In other words, before treatment these patients already have an IGF-I that would be regarded as satisfactory response to GH replacement therapy. Prima facia, it is difficult to reconcile a serum IGF-I within the reference range and a diagnosis of GHD. Inevitably, it poses the question if factors other than GH are regulating circulating IGF-I levels in such patients.

Pegvisomant is a GH analogue that binds to, but does not activate the GH receptor and has been shown to normalise IGF-I in up to 97% of patients with acromegaly (20). We used pegvisomant to study the relationship between GH and IGF-I in patients with severe adult GHD and investigate whether IGF-I in such patients, is particularly GH-dependent.

Study Type : Interventional  (Clinical Trial)
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double
Official Title: A Study of the Relationship Between Serum Growth Hormone (GH) and Insulin-Like Growth Factor One (IGF-I) in Patients With Severe Adult Growth Hormone Deficiency (AGHD)
Study Start Date : December 2004
Actual Study Completion Date : July 2005

Primary Outcome Measures :
  1. change in IGF-I [ Time Frame: 2 weeks per limb ]

Secondary Outcome Measures :
  1. change in basal and stimulated GH Change in IGFBP-3 Change in GHBP [ Time Frame: 2 weeks per limb ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Over 18 years of age
  • Confirmed severe AGHD
  • GH response <9 mU/l (preferably <4) to insulin-induced hypoglycaemia or glucagon stimulation test plus (These tests will have taken place as part of routine management).
  • Full, stable pituitary replacement therapy
  • Willing to provide informed consent

Exclusion Criteria:

  • Unwilling to provide written consent
  • Current GH therapy
  • Pharmacological doses of glucocorticoids
  • Any acute illness

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00468624

United Kingdom
Christie Hospital NHS Trust
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
The Christie NHS Foundation Trust
Principal Investigator: Peter J Trainer, MD FRCP Christie Hospital NHS

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Other Study ID Numbers: 04_ENDO_41
First Posted: May 3, 2007    Key Record Dates
Last Update Posted: May 3, 2007
Last Verified: May 2007

Keywords provided by The Christie NHS Foundation Trust:
Growth hormone
insulin-like growth factor 1

Additional relevant MeSH terms:
Endocrine System Diseases
Dwarfism, Pituitary
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Bone Diseases, Endocrine
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs