Review
Diagnosis of adult GH deficiency

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Abstract

The current guidelines for the diagnosis of adult GHD are mainly based on the statements from the GH Research Society Consensus from Port Stevens in 1997. It is stated that diagnosis of adult GHD must be shown biochemically by provocative tests within the appropriate clinical context. The insulin tolerance test (ITT) was indicated as that of choice and severe GHD defined by a GH peak lower than 3 μg/L. The need to rely on provocative tests is based on evidence that that the measurement of IGF-I as well as of IGFBP-3 levels does not distinguish between normal and GHD subjects. Hypoglycemia may be contraindicated; thus, alternative provocative tests were considered, provided they are used with appropriate cut-off limits. Among classical provocative tests, arginine and glucagon alone were indicated as alternative tests, although less discriminatory than ITT. Testing with the combined administration of GHRH plus arginine was recommended as an alternative to ITT, mostly taking into account its marked specificity. Based on data in the literature in the last decade, the GRS Consensus Statements should be appropriately amended. Regarding the appropriate clinical context for the suspicion of adult GHD, one should evaluate patients with hypothalamic or pituitary disease or a history of cranial irradiation, as well as those with childhood-onset GHD are at obvious risk as adults for severe GHD. Brain injuries (trauma, subarachnoid hemorrage, tumours of the central nervous system) very often cause acquired hypopituitarism, including severe GHD. Given the epidemiology of brain injuries, the important role of the endocrinologist in providing major clinical benefit to brain injured patients who are still undiagnosed should be underscored. From the biochemical point of view, although normal IGF-I levels do not rule out severe GHD, very low IGF-I levels in patients highly suspected for GHD (i.e. patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood) can be considered as definitive evidence for severe GHD; thus, these patients would skip provocative tests. Patients suspected for adult GHD with normal IGF-I levels must be investigated by provocative tests. ITT remains a test of reference but it should be recognized that other tests are as reliable as ITT. Glucagon as classical test and, particularly, new maximal tests such as GHRH in combination with arginine or GH secretagogues (GHS) (i.e. GHRP-6) have well defined cut-off limits, are reproducible, able to distinguish between normal and GHD subjects. Overweight and obesity have confounding effect on the interpretation of the GH response to provocative tests. In adults cut-off levels of GH response below which severe GHD is demonstrated must be appropriate to lean, overweight and obese subjects to avoid false positive diagnosis in obese adults and false negative diagnosis in lean GHD patients. Finally, normative values of GH response to provocative tests may depend on age, particularly in the transitional age; the normative cut-off levels of GH response to ITT in this phase of life are now available.

Introduction

Adults with growth hormone deficiency (GHD) have impaired health, which improves with GH replacement. GHD in adults leads to impairment in body composition and function, as well as to deranged lipoprotein and carbohydrate metabolism and increased cardiovascular morbidity [1], [23], [28], [29], [30]. Based on evidence that GHD in adults is a new syndrome which may benefit from GH replacement, health authorities in many countries have approved the therapeutic use of GH in hypopituitaric patients with severe GHD [55], [85].

To ensure that patients are appropriately identified and treated, the Growth Hormone Research Society (GRS) convened a workshop on 1997, in Port Stephens, Australia, to formulate consensus guidelines for the diagnosis and treatment of adults with GH deficiency. The GRS invited scientists with appropriate expertise, representatives from industry involved in the manufacture of recombinant human GH, and representatives from health authorities from a number of countries to attend the workshop, all of whom contributed to these guidelines [55].

During the last decade, there is evidence indicating that the guidelines for the clinical management of adult GHD should be amended and this prompted the Growth Hormone Research Society (GRS) to convene a second workshop in Sydney, Australia, in March, 2007.

Section snippets

Diagnosis of adults GHD: current guidelines

We report the most important statements of the 1997 GRS Consensus about the diagnosis of adult GHD (in italics). Appropriate amendments (in bold) are stated.

Who should be tested: expanding the concept of appropriate clinical context to brain injury

In adulthood, hypopituitarism and GH deficiency (GHD) are more often “acquired” as consequences of hypothalamic-pituitary disease [35], [55], [85] or represent the persistence of a congenital or acquired pituitary defect diagnosed in childhood [27], [95]. Multiple pituitary deficits are often present, but isolated pituitary deficits are not uncommon. Among them, GH is usually the first of the anterior pituitary hormones to be affected [55], [85]. Thus, GHD can be considered to indicate possible

Conclusions

Ten years after, the GRS Consensus Statement requires some amendment.

From the diagnostic point of view, it is suggested that the new guidelines express:

  • (a)

    The concept of appropriate clinical context indicating the suspicion of adult GHD (i.e. patients with hypothalamic or pituitary disease or cranial irradiation as well as those with childhood-onset GHD) is extended to include brain injured patients.

  • (b)

    It is accepted that very low IGF-I levels in patients highly suspected for GHD (i.e. patients with

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