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Diagnosis of adult GH deficiency


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doi:10.1016/j.ghir.2007.07.004

Copyright ? 2007 Elsevier Ltd All rights reserved.

 

Review

 

Diagnosis of adult GH deficiency

 

E. Ghigoa, Corresponding Author Contact Information, E-mail The Corresponding Author, G. Aimarettib and G. Cornelib

 

aDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, C. so Dogliotti 14, 10126 Turin, Italy

 

bEndocrinology, Department of Clinical and Experimental Medicine, University of Eastern Piedmont, Via Solaroli 17, 28100, Novara, Italy

 

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 ug/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.

 

Keywords: GH; IGF-I; IGFBP-3; Adult GH deficiency; Diagnosis

 

Article Outline

 

1. Introduction

2. Diagnosis of adults GHD: current guidelines

 

2.1. Definition of adult GH deficiency

2.2. Patients who should be tested for adult GH deficiency

2.3. Biochemical diagnosis of adult GH deficiency

 

3. Key issues for updated guidelines: TBI

 

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

3.2. Diagnostic value of IGF-I measurement

3.3. Other biochemical parameters for the diagnosis of adult GHD

3.4. Provocative tests alternative to ITT

3.5. Diagnosis of GHD in obese subjects

3.6. Diagnosis of GHD in the transition period adolescent-to-young adult

 

4. Conclusions

 

References

 

1. 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] and [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] and [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.

 

2. 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.

2.1. Definition of adult GH deficiency

 

Severe GH deficiency should be defined biochemically within an appropriate clinical context.

 

The concept of appropriate clinical context (see below) should be expanded.

 

Partial GH deficiency exists, but further research is needed to distinguish it from physiological causes of reduced GH secretion, e.g. aging. Furthermore, the benefits of treatment of partial GH deficiency remain to be established.

 

Some studies about partial GHD in adults have shown that GH insufficiency, although not severe, is associated with a derangement in lipid profile and cardiac performance [1], [28], [29], [30], [31], [86] and [87]. However, the benefits of rhGH replacement have not yet been demonstrated.

2.2. Patients who should be tested for adult GH deficiency

 

An evaluation for GH deficiency should be considered only in patients with evidence of hypothalamic-pituitary disease, subjects who have received cranial irradiation, or patients with childhood onset of GH deficiency.

 

In patients with organic hypothalamic-pituitary disease, the likelihood of GH deficiency increases with the increasing number of pituitary hormone deficits from approximately 45% if no other deficits are present to nearly 100% if three or four pituitary hormone deficiencies are present. It may not be necessary to evaluate patients with pituitary microadenomas for GH deficiency unless other pituitary hormone deficits are present or unless a strong clinical suspicion of GH deficiency exists. Patients with childhood-onset GH deficiency should be retested as adults before committing them to long-term GH replacement.

 

As anticipated, the concept of appropriate clinical context to suspect severe GHD in adults has to be expanded (see below) to include brain injured individuals as subjects at high risk for acquired hypopituitarism, including severe GHD [2], [3], [4], [16], [19], [24], [38], [50], [67], [69], [71], [72], [96] and [101].

2.3. Biochemical diagnosis of adult GH deficiency

 

Dynamic tests of GH secretion.

 

The diagnosis of adult GH deficiency is established by provocative testing of GH secretion.

 

This statement should be softened, taking into account studies showing that, although normal IGF-I levels do not rule out severe GHD, very low IGF-I levels in patients highly suspected for GHD can be taken as definite evidence for severe GHD [9], [10], [11], [12], [14], [45], [46], [58], [84] and [85]. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple anterior pituitary hormone deficits acquired in adulthood (see below).

 

Patients should be receiving stable and adequate hormone replacement for other hormonal deficits before testing.

 

At present, the insulin tolerance test is the diagnostic test of choice. Provided adequate hypoglycemia is achieved, this test distinguishes GH deficiency from the reduced GH secretion that accompanies normal aging and obesity. The insulin tolerance test should be performed in experienced endocrine units where the test is performed frequently. The test is contraindicated in patients with electrocardiographic evidence or history of ischemic heart disease or in patients with seizure disorders. Given these precautions, the insulin tolerance test is safe; however, there is less experience in patients over the age of 60 yr.

 

Most normal subjects respond to insulin-induced hypoglycemia with a peak GH concentration of more than 5 ?g/L. Severe GH deficiency is defined by a peak GH response to hypoglycemia of less than 3 ?g/L.

 

These cut-off values were defined in GH assays employing polyclonal competitive RIAs. However, GH immunoassay results vary between different methods, and therefore, the cut-off value may need to be adjusted appropriately.

 

In patients with contraindications to the insulin tolerance test, alternative provocative tests of GH secretion must be used with appropriate cut-offs.

 

At present, the combined administration of arginine and GHRH is the most promising alternative.

 

This statement should be modified taking into account that GHRH + arginine test is now more than simply the most promising alternative [11], [17], [45],[46] and [85]. Also the reliability of testing with GHRH + GH Secretagogues should be accepted as well [46], [85], [88], [89] and [91] (see below).

 

Administration of arginine alone or glucagon alone can be considered, but these tests have less established diagnostic value compared to the insulin tolerance test. Other stimulatory tests may prove to be useful, but require further validation. The present data indicate that the clonidine test is less useful in adults than in children.

 

This statement would be modified too, taking into account that, among other classical provocative tests, normative values and diagnostic reliability have been defined for glucagon test only [7], [32] and [53]; the diagnostic reliability of arginine alone has been questioned [7], [17] and [85] (see below).

 

Adult patients with hypothalamic-pituitary disease and one or more additional pituitary hormone deficits require only one provocative test of GH secretion for the diagnosis of GH deficiency.

 

Childhood-onset GH deficiency requires reconfirmation in adulthood. To establish the diagnosis of isolated GH deficiency in adults, it is recommended that, in addition, a second biochemical test of GH status be abnormal.

 

The need of two provocative tests to confirm severe GHD should be reconsidered. We propose that reconfirmation of adult GHD in childhood-onset GHD would base on one single provocative test and perhaps even on the demonstration of very low IGF-I levels only, particularly when multiple pituitary deficits are present [5], [15] and [65] (see below).

 

Biochemical markers of GH action

 

Several biochemical markers of GH action have been studied to determine their diagnostic potential in adult GH deficiency.

 

Serum insulin-like growth factor I (IGF-I) concentrations are only useful when age-adjusted normal ranges are available. In adults, a normal serum IGF-I does not exclude the diagnosis of GH deficiency. A serum IGF-I below the normal range is suggestive of GH deficiency in the absence of other conditions known to lower serum IGF-I levels; for example, malnutrition, hepatic disease, poorly controlled diabetes mellitus, and hypothyroidism. In the presence of multiple (two or more) pituitary hormone deficiencies, a low serum IGF-I level indicates a high probability of GH deficiency. However, it is recommended that the diagnosis of adult GH deficiency be confirmed by a provocative test of GH release.

 

As anticipated, this statement has likely to be modified taking into account studies showing that, although normal IGF-I levels do not rule out severe GHD, very low IGF-I levels in patients highly suspected for GHD could be considered definite evidence for severe GHD [9], [10], [14], [46] and [58]. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood who would skip provocative test if very low IGF-I levels are demonstrated [5], [15] and [65] (see below).

 

Standardization of assays

 

GH immunoassay results vary between different assay methods. The above recommendations for cut-off values for the insulin tolerance test are based on results obtained with polyclonal competitive RIAs calibrated against the pituitary-derived preparation International Reference Preparation (IRP) 80/505 (1 mg = 2.6 U). The GRS advocates future use of the recombinant hGH preparation IRP 88/624 (1 mg = 3.0 U). Further comparative studies are necessary at both national and international levels to achieve standardization of GH assays.

 

The presence of IGF-binding proteins interfere with measurement of serum IGF-I. At present, removal of IGF-binding proteins before immunoassay is essential. However, new IGF-I assays are being developed that may not require extraction procedures. The current international reference standard for IGF-I assays is IRP 87/518. GH and IGF-I results should be expressed in mass units.

 

The issue of standardization is still a problem and little progress has been made in the last decade. It remains that the recommendations should be done for cut-off values of GH and IGF-I in general without restricting to GH peak after ITT. Also, hormonal levels should always be expressed in mass units, i.e. mcg/L instead of Units [94].

3. Key issues for updated guidelines: TBI

3.1. 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] and [85] or represent the persistence of a congenital or acquired pituitary defect diagnosed in childhood [27] and [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] and [85]. Thus, GHD can be considered to indicate possible impaired pituitary function, which could evolve to include other pituitary axes.

 

Adult patients who have hypothalamic-pituitary masses either before or after therapy (neurosurgery and/or radiotherapy and/or medical therapy) are at high risk for severe GHD (more than 80%). Thus, these patients are at "obvious" risk for severe GHD and routine evaluation of their pituitary function is mandatory [35] and [85]. The same statement applies to patients who had been diagnosed as having either congenital or acquired GHD in childhood [27]. The large majority (more than 90%) of patients with childhood-onset multiple hypopituitarism show persistent severe GHD at retesting as adults. On the other hand, among patients who had been treated with rhGH for isolated GHD in childhood a lower percentage (varying between 30 and 70%) shows persistence of severe GHD at retesting in adulthood [5], [15], [22], [39], [52], [65], [73], [82], [98], [102], [103], [110] and [112].

 

Such adolescents and adults must always undergo biochemical investigation to clarify whether severe GHD persists.

 

Recently it has been demonstrated that other common pathological conditions of the CNS, such as traumatic brain injury, subarachnoid haemorrhage or primary brain tumours are also associated with high risk for GHD [2], [3], [4], [16], [19], [24], [38], [50], [67], [69], [71], [72], [96] and [101].

 

Indeed, pituitary function is impaired in approximately 50% of patients with primary brain tumours, likely as a consequence also of neurosurgery and radiotherapy [96]. Hypopituitarism in patients with primary brain tumours often includes severe GHD and this has clinical implications that should be carefully considered for therapy with rhGH [96]. That treatment of severe GHD provides benefit for patients with primary brain tumours and is devoid of any safety problem has, however, yet to be demonstrated.

 

On the other hand, acquired hypopituitarism associated with traumatic and vascular brain injuries implies more relevant clinical implications. The peculiar anatomical and vascular structure of the hypothalamic-pituitary unit predicts its fragility and the risk for traumatatic damage. Previous autopsy studies had demonstrated that 30?50% of the patients who had fatal head trauma showed various extent of pituitary infarction and/or hypothalamic microhaemorragies. After many case reports of traumatic brain injured (TBI) patients that were reviewed by Benvenga et al. [16], Lieberman et al., showed high prevalence of neuroendocrine dysfunction in TBI patients during the rehabilitation period with a frequency of GHD as high as 15% and low cortisol levels in 46% of the patients [72]. Pituitary deficits would therefore have important implication for patients' health, sense of well-being, and rehabilitation potential. The same message has come from the study of Kelly et al. who demonstrated that hypopituitarism and GHD may occur also after acute vascular injuries, such as subarachnoid haemorrhage (SAH) secondary to rupture of cerebral aneurysm [67] and [69]. SAH would impair pituitary function given the proximity of these structures to Circle of Willis vessels and the potential of vasospasm of the feeding branches to the hypophyseal vasculature [68]. As the majority of patients with SAH have persistent neurobehavioral and quality of life problems, it is of major importance to consider the possibility that pituitary deficits would have significant health-related implications.

 

These observations have been confirmed by several studies, indicating also that acquired hypopituitarism is not strictly associated to the severity of the brain injury [4] and [101]. The percentage of patients with varying degrees of hypopituitarism after TBI or SAH varied between 22.7% and 68.5% with approximately 10% of patients with panhypopituitarism. The percentage of patients with GH deficiency ranged from 9 to 28%, evaluated depending on which provocative tests (ITT, GHRH + Arginine, Glucagon, GHRH + GHRP6) were done. However, most of the studies were primarily retrospective with various time after the brain injury [16], [67], [69], [71] and [72]; however, the same picture has been confirmed in prospective studies [4] and [101] showing also that panhypopituitarism is invariably maintained at follow-up. Thus, there is now wide agreement about the clinical relevance of brain injury-induced anterior pituitary dysfunction and GH deficiency. It is clear that target organ hormones must always be appropriately replaced. However, the current hypothesis is that appropriate hormonal replacement may even provide improvement of symptoms related to the post-traumatic syndrome as well as the recovery phase.

 

Most of all, the relevance of this clinical problems is strengthened by the epidemiology of traumatic brain injury. For example, in Italy, the admission to Hospital of TBI patients is: 300/100,000/yr with a mortality of 20/100,000/yr. If we consider that even 10% only out of TBI patients would have acquired hypopituitarism including GHD, we could foresee 300 hypopituitary patients per year (i.e. 3000 in the last 10 years) in a city of 1,000,000 people [100].

 

In all, it is clear that the endocrine evaluation is mandatory in the clinical management of patients who have suffered brain injury. All these patients should be carefully followed-up to disclose hypopituitarism, including severe GHD. To perform the clinical screening for hypopituitarism in brain injured patients tight collaboration of endocrinologists with neurosurgeons, intensive care and rehabilitation doctors is recommended.

 

Recently, some studies have reported that hyperparathyroidism is often associated with impairment of somatotropic function that may be as severe as that in patients with panhypopituitarism [44]. The clinical relevance of this alteration has, however, to be clarified. Severe impairment of the GH response to provocative tests has been demonstrated in patients with primary empty sella independently of body weight that is often enhanced in this common clinical condition [42]. Again, it remains to be clarified if diagnosis and treatment of patients with severely impaired GH response to provocative tests provides any benefit to those with primary empty sella.

3.2. Diagnostic value of IGF-I measurement

 

The 1997 guidelines from the GH Research Society state that the diagnosis of adult GHD has to be always shown biochemically by provocative tests within the appropriate clinical context.

 

The need to rely on provocative tests is based on evidence that the measurement of IGF-I as well as of IGFBP-3 levels do not distinguish between normal and GHD subjects. In agreement with the inability of the study of 24 h mean GH concentration to distinguish between normal and GHD adults [13] and [46], also the measurement of total IGF-I levels, the best marker of the GH status [54], shows considerable overlap between the two groups [9], [10], [11], [25], [55], [84] and [85]. Thus, normal levels of IGF-I do not rule out the existence of severe adult GHD [9], [14], [84] and [97]. This also holds for measures of free IGF-I levels [65] and [84].

 

In a study in a large population of panhypopituitaric adults with severe GHD (as demonstrated by the severe impairment of the GH response to GHRH + arginine test), we found that a large percentage of the patients have total IGF-I levels within the age-related normal range [9] and [11].

 

Age is a variable partially explaining the overlap between total IGF-I levels in normal and severely GHD subjects [9], [14], [46], [54], [59] and [104]. Total IGF-I levels progressively decrease with aging reflecting the age-related decrease in GH secretion [104]; in fact, the most remarkable overlap between normal and GHD subjects in term of total IGF-I levels occurs in the aging population [9], [11], [12], [14] and [59].

 

Taking into account the major role played by insulin and the nutritional status in the regulation of IGF-I synthesis and secretion, the presence of overweight and hyperinsulinism in hypopituitary patients with GHD likely plays a critical role. In fact, patients with simple obesity generally have normal levels of total IGF-I and even increased levels of free IGF-I, despite significant GH insufficiency that is sometimes as marked as in hypopituitary patients with severe GHD [75] and [76]. In agreement with this hypothesis, mean total IGF-I levels in hypopituitary patients with severe GHD and overweight are higher than in GHD patients with normal body weight [12]. The percentage of IGF-I levels below the age-related normal limits in GHD adults with normal body weight is higher than in overweight patients [12].

 

Thus, it is possible that the common occurrence of overweight, insulin resistance and hyperinsulinism in GHD adults, despite the severe impairment of somatotroph function, is able to allow low normal IGF-I synthesis and secretion. In fact, patients with simple obesity have increased IGF-I response to a very low rhGH dose, indicating that obesity may increase GH sensitivity [77] and [111].

 

Other factors may explain such a high percentage of severe GHD adults with total IGF-I levels within the normal range; for example, adults with severe GH but normal IGF-I levels have peculiar feature of 24 h spontaneous GH secretion including an increase in GH burst frequency coupled with reduced GH burst amplitude and positive association between apparent entropy (ApEn) a measure of the regularity of GH secretion and total IGF-I levels [99].

 

Again, also a short duration of the disease and a low number of anterior pituitary deficits are associated with higher IGF-I levels [10], [15], [55], [58] and [105].

 

From the clinical point of view, independent of the mechanisms explaining the high frequency of normal levels of total IGF-I in the presence of severe GHD in hypopituitary adults, there is general agreement that within the appropriate clinical context, despite normal levels of total IGF-I, adults suspected for severe GHD must undergo provocative tests to clarify the diagnosis [9], [11], [45], [46], [55] and [85].

 

However, before completely ruling out the diagnostic value of the measurement of total IGF-I, one must consider that, at least in well nourished subjects without liver disease or hypothyroidism, evidence of low IGF-I levels strongly predicts severe GHD [9], [14] and [58]. In adult GHD, it had been demonstrated that multiple pituitary deficits and childhood-onset GHD are associated to the lowest levels of total IGF-I [5] and [15]. Moreover, total IGF-I is a parameter with good intra-individual reproducibility and positively associated to the peak GH response to provocative tests [14].

 

The possibility that very low IGF-I levels would represent definite evidence for severe adult GHD had been considered also in the Consensus Guidelines for adult GHD generated by the GH Research Society in 1997 [55]. This has been demonstrated by more recent studies [9], [10] and [58].

 

By analyzing the clinical characteristics and biochemical testing results of 817 patients with a history of either adult-onset hypothalamic or pituitary disease or childhood-onset GHD, Hartman et al. [58] found that adult GHD could be predicted with 95% accuracy by the presence of either three or four pituitary hormone deficits (PHDs) or a serum IGF-I concentration less than 84 ?g/L (11 nmol/L). Based on these results, the authors proposed that adult patients with three or four pituitary deficits and low IGF-I levels do not require a GH stimulation test to make the diagnosis of adult GHD. These clinical predictors are considered at least as accurate as GH stimulation tests performed in routine clinical practice. The diagnostic utility of a cut-off limit as IGF-I less than 84 ?g/L to predict adult GHD is limited to the particular IGF-I assay employed in this study. The same concept, however, has been followed by other authors who recommended that the IGF-I cut-off limit is expressed in standard deviation units evaluated in an appropriate reference population of normal subjects. By following this approach, cut-off limits of -2 SD [54] and [59] or ranging from -1.65 to -1.80 for GHD adults whose disease had adult- or childhood-onset, respectively [21] have been proposed. Once again, the diagnostic reliability was particularly satisfactory when patients with childhood-onset severe GHD or multiple pituitary deficits were considered [21], [54] and [59]. The same picture was not confirmed by others who found diagnostic sensitivity of total IGF-I levels was approximately 40% [84].

 

In a large population of panhypopituitaric patients with severe GHD, Aimaretti et al. [9] showed that a considerable percentage of patients, particularly below 40 yr of age, have total IGF-I levels below the age-related normal limits. Thus, it seemed reasonable to recognize that, within the appropriate clinical context, low total IGF-I levels have a definite diagnostic value.

 

In all, it is proposed that the revised Guidelines recognize that very low total IGF-I levels (below 2 SD) in subjects highly suspected for GHD (patients with childhood-onset, isolated GHD or multiple hypopituitarism or with long-lasting adult-onset multiple or total hypopituitarism) are considered definite evidence of severe GHD; these patients would therefore skip provocative tests.

3.3. Other biochemical parameters for the diagnosis of adult GHD

 

As anticipated above, the measurement of free IGF-I levels does not offer any significant advantage compared to determination of total IGF-I levels for the diagnosis of adult GHD [46], [64], [84] and [85]. In a study where the measurement of free IGF-I levels was compared also with IGFBP-3, as another potential diagnostic parameter, it was concluded that free IGF-I measurement did not offer advantage even over IGFBP-3 [64].

 

IGFBP-3 is the most abundant circulating IGFBP, is mostly GH dependent and has been considered by some as another reliable marker of the GH status [84]. However, it is less sensitive to GH than IGF-I and the measurement of IGFBP-3 does not provide any advantage over total IGF-I for the diagnosis of adult GHD [25] and [84]. The urinary measurement of IGFBP-3 as well as of IGF-I offered results even more disappointing [41] and [54]. Also, the hypothesis that the combined evaluation of IGF-I and IGFBP-3 and/or its ratio provide further diagnostic power for adult GHD has been proposed by some but ruled out by many others [84].

 

The acid-labile subunit (ALS) is a glycoprotein that binds IGF-I together with IGFBP-3 to form a trimeric complex; it is GH dependent but, like IGFBP-3, does not reflect the GH status as accurately as IGF-I. ALS measurement had been proposed as alternative parameter for the diagnosis of adult GHD but the large majority of the authors agree that it does not offer any advantage over total IGF-I, at least for the diagnosis of adult GHD [40] and [84].

3.4. Provocative tests alternative to ITT

 

The 1997 guidelines stated that insulin tolerance test (ITT) is the gold standard test for the biochemical demonstration of severe GHD in adults. The statements about the reliability of ITT can still be accepted as they are [45], [55] and [85], although some concerns about its reproducibility and specificity have been reported [60], [63] and [109]. The same applies for contraindications to ITT that include patients with electrocardiographic evidence or history of ischemic heart disease and patients with seizure disorders; it should be emphasized that they should include also brain injured patients and elderly subjects [50].

 

In agreement with the cut-off level indicated by the GRS guidelines in 1997, data from Aimaretti et al [7] and [11] demonstrated that 3 and 5 ?g/L represent the first and the third centile limit of the GH peak response in normal lean subjects.

 

Based on data from Biller et al., the opportunity to increase the cut-off limit of GH peak response to ITT below which severe GHD is demonstrated from 3 to 5 ?g/L would be considered [17]. In fact, in this study a cut-off level of 5.1 ?g/L showed the best pair of sensitivity and specificity (96% and 92%, respectively) as evaluated by the ROC curve analysis. Moreover, in this study as well as in that from Hoffman et al. [61] the control group included also obese subjects that generally show remarkable decrease of the GH response to all known provocative stimuli [20], [33], [51], [56], [66], [75], [78], [92] and [93]. The lack of normative cut-off values by BMI has clinical implications (see below in Diagnosis of GHD in obesity).

 

We recommend that alternative provocative tests should be used with appropriate cut-off limits. Among "classical" provocative tests alternative to ITT, glucagon as well as arginine test had been suggested in the 1997 guidelines, although more extensive validation was not provided.

 

The glucagon test has been confirmed as a reliable diagnostic test and the cut-off level of 3 ?g/L shows the best pair of sensitivity (100 and 97%, respectively in two different studies) and specificity (100 and 88%, respectively in two different studies) as evaluated by the ROC curve analysis [32] and [53]. Indeed, the GH-releasing action of glucagon is, at least, equal to that of ITT [7]. This test is still widely used and the clinicians should be allowed to consider this test as reliable as ITT.

 

The reliability of arginine alone as provocative test has been studied by Biller et al. who found that the best pair of sensitivity and specificity (87 and 91%, respectively) is shown by a cut-off level of 0.4 ?g/L. In this study, the control group included obese subjects and it is known that the somatotropic response to this stimulus is strongly reduced by overweight; this would have a role in such a low cut-off level defined by that study [17] and [85]. However, the mean GH response to arginine alone is lower than that recorded after ITT or glucagons even in normal lean subjects [7]. Thus, testing with arginine alone should not be considered a reliable alternative test for the diagnosis of adult GHD.

 

In all, ITT and glucagon are the only classical provocative tests that are reliable for the diagnosis of adult GHD. The cut-off levels of the GH response to these tests have, however, never been validated by BMI and this would have some clinical relevance (see below).

 

In the 1997 guidelines, the combined administration of arginine and GHRH was defined as the most promising alternative to ITT. This statement should be modified taking into account that GHRH + arginine test has now been clearly validated.

 

The normal limits of the GH response to this test and its within-subject reproducibility had been very well defined in a large cohort of normal subjects. In this population the third centile limit of the normal peak GH response was 16.5 ?g/L, while the first centile was 9.0 ?g/L. No significant gender- or age-related differences were found. The mean peak GH response to GHRH + arginine was clearly higher than that to the majority of other classical provocative tests. The low intra-individual variability of the GH response to GHRH + arginine in two testing sessions was demonstrated in adult and elderly normal subjects as well as in patients with severe GHD [46], [47], [49] and [106].

 

It has been demonstrated by Aimaretti et al. [11] that the GHRH + ARG test distinguishes adult GHD patients from normal subjects and that it is at least as sensitive as ITT, provided that appropriate cut-off limits are considered. This study showed also the strict positive association between the peak GH response to GHRH + ARG and ITT in hypopituitaric patients with GHD [11] and [14]. With respect to appropriate first centile cut-off limits, GHD was shown in approximately 80% and 90% of patients by ITT and GHRH + ARG, respectively [11].

 

It has also been demonstrated that, given appropriate cut-off limits, GHRH + ARG is as reliable as ITT for retesting patients who had rhGH treatment in childhood. Severe GHD in adulthood was confirmed by GHRH + ARG test as well as by ITT in more than 90% of patients with organic GHD and in more than 50% of patients who had been diagnosed as severe, idiopathic GHD [5].

 

Further agreement about the assumption that GHRH + ARG test is as reliable as ITT for the diagnosis of adult GHD comes from data from Biller and co-workers who had normal control subjects matched to the pituitary patients for age, sex and even BMI [17]. The relevance to define the cut-off levels by BMI is discussed in the following section.

 

Another important point favoring GHRH + ARG as first-choice test is its very good safety profile and the lack of contraindications notable exception being chronic renal failure.Moreover, it has been demonstrated that the procedure of GHRH + arginine test in clinical practice can be usefully shortened, evaluating GH levels at three time points only and in a single session; this procedure clearly simplifies the clinical practice and reduces logistical problems and costs [8].

 

Another provocative test that has been proposed and extensively studied is the association of GHRH with a synthetic GH Secretagogue such as GHRP-6 or alternatively Hexarelin and GHRP-2 [46] and [3]. This combined test represents the same approach of GHRH in combination with arginine where the amino acid is replaced by a synthetic GHS, a non-natural molecules that mimics the activity of the natural GHS receptor ligand (i.e. ghrelin) [6], [46] and [88]. Like arginine, GHS and GHRH have a true synergistic effect determining strong GH-releasing effect [46], [88] and [89]. Like GHRH + ARG, GHRH + GHRP-6 shows good intra-individual reproducibility [91], is partially refractory to the inhibitory effect of glucose and free fatty acid load as well as of rhGH [46]. The GH response to GHRH + GHS is dependent on aging being reduced in elderly subjects [46], [56] and [88] and is likely to be negatively associated to BMI being reduced in obese patients [33], [34], [56] and [66]; nevertheless, in aged and obese subjects, testing with GHRH + GHS shows an impressive GH discharge indicating its potency as provocative stimulus.

 

Normal values and reproducibility of testing with GHRH plus low-dose hexarelin in normal young adults were reported [7] and [43]. Moreover, in a large group of hypopituitary patients with severe GHD, this test was as reliable as ITT and GHRH + ARG although referring to different cut-off limits appropriate to each test [43]. In another study testing with GHRH + GHRP-2 demonstrated its diagnostic reliability with 100% specificity and 78.6% sensitivity even taking into account single GH measurement 30 min after drug administration [83]. Ghrelin itself, the natural ligand of the GHS receptor, is likely to represent a good provocative test to evaluate somatotroph function [6] but normative data are still lacking. The reliability of testing with GHRH + GHRP-6 has been more extensively validated in comparison to ITT by Popovic and Casanueva [88]. In their study, 125 adult patients with organic pituitary disease and 125 healthy individuals were evaluated. Inclusion criteria were severe GH deficiency demonstrated by a GH peak after ITT of less-than-or-equals, slant3 ?g/L. The results of the GHRH/GHRP-6 test were analyzed by ROC curve analysis. The GH mean peak after the GHRH/GHRP-6 test was markedly higher than that after ITT. GH peak levels showed a continuum, from 139.0 ?g/L to 0.01 ?g/L, with a cut-off point of 15.0 ?g/L. The GHRH/GHRP-6 test performed well under the ROC curve analysis. For clinical utility, it has been proposed that values greater-or-equal, slanted20.0 ?g/L be considered normal and less-than-or-equals, slant10.0 ?g/L as GH deficient. An evoked GH concentration of greater-or-equal, slanted15.0 ?g/L accurately distinguishes between healthy and GH-deficient adults but patients suspected for hypopituitarism with a GHRH + GHRP-6-induced GH peak between 10 and 20 ?g/L, the authors proposed that the final diagnosis would be based either on considering the appropriate clinical context or doing a second provocative test [88]. In other studies the parallel reliability of GHRH + GHRP-6 and GHRH + ARG in comparison to ITT has also been demonstrated [89].

 

Similar to GHRH + ARG, GHRH + GHRP-6 shows very good safety profile and no contraindications [88] and [89]. Moreover, this test too would be performed in a shortened procedure evaluating GH levels at one single time point and in a single session [70].

 

This way of approaching the evaluation of somatotropic function by administration of GHRH in combination with GHRP-6 as well as with arginine raised some concerns about potential limits.

 

As GHRH acts directly on the pituitary, its administration even in combination with molecules such as GHRP-6 or arginine could induce clear GH response even in hypopituitary patients with GHD due to a hypothalamic GHRH deficit [37] and [90]. Some studies have been performed to clarify this point.

 

Maghnie et al [81] studied the relationship between hypothalamic-pituitary morphology and somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool. The GH-releasing effect of GHRH + ARG was studied in patients with congenital GHD according to their pituitary magnetic resonance imaging findings, consisting of anterior pituitary hypoplasia, stalk agenesis (neural and or vascular component), and ectopic posterior pituitary. Partial integrity of the hypothalamic-pituitary connections is essential for GHRH + ARG to express its full GH-releasing activity. The test was fully reliable in the diagnosis of congenital hypopituitarism in both patients with complete pituitary stalk agenesis and MPHD. Some false negative responses occurred with this test in subjects with congenital GHD, but less severe impairment of the pituitary stalk. However, the test generally displayed very good sensitivity for the diagnosis of adult GHD.

 

Similar results were reported by Maghnie et al. [80] in children with acquired GHD deficiency including idiopathic inflammatory pituitary stalk involvement, Langerhans cell histiocytosis affecting the hypothalamic-pituitary area and craniopharyngioma. This study confirmed the diagnostic potential of the GHRH + ARG test in children with acquired GH deficiency caused by hypothalamic-pituitary lesion. The stimulatory effect of GHRH + ARG on GH secretion was greater in patients with hypothalamic GHD deficiency than in those with both hypothalamic and pituitary lesions. Some false negative responses to GHRH + ARG test occurred in patients with hypothalamic GHD only.

 

As cranial radiotherapy is frequently cause of acquired "hypothalamic" GHD, Darzy et al. [37] compared the results obtained by ITT and GHRH + ARG in adult survivors (aged 16?53.7 yr), who were previously irradiated for non-pituitary brain tumours or leukemia, and age-, gender-, and BMI-matched controls. The GH response to both tests was lower in the patients than in normal individuals. Either in patients or in controls the GH response to GHRH + ARG was higher than that to ITT. The ratio between GHRH + ARG and ITT was higher in the patients than in controls in the first five years after irradiation. The GH response to ITT in irradiated patients declined within five years while that to GHRH + ARG declined up to 10 years after irradiation when the concordance between the two tests was maximal. In the whole group, the peak GH response to ITT and GHRH + ARG showed, however, strong positive correlation. The authors concluded that hypothalamic dysfunction occurs early and pituitary dysfunction occurs later following radiation damage. The time dependency of somatotroph dysfunction may reflect either secondary somatotroph atrophy due to hypothalamic GHRH deficiency or delayed direct radiation-induced damage to the pituitary gland. In the first years after cranial irradiation, the ITT is more reliable than GHRH + ARG to explore the GH status as a consequence of hypothalamic impairment. The same conclusions were stated by Ham et al. [57] who studied the GH response to GHRH + ARG in comparison to ITT in medulloblastoma survivors who had previously had cranio-spinal irradiation.

 

Finally, Bjork et al. [18] investigated the sensitivity and specificity of the GHRH + ARG test using ITT as the gold standard in diagnosing GHD in a group of young adults treated with cranial irradiation for childhood acute lymphoblastic leukemia. Because a high proportion of GHD patients showed a normal response to the GHRH + ARG test, the authors concluded it cannot be used reliably to exclude GHD in irradiated patients who otherwise should be tested again by ITT to rule out severe GHD.

 

The influence of cranial irradiation on the GH response to GHRH + GHRP-6 test was also investigated by Popovic et al. [90] in adult patients who received cranial radiation for primary brain tumours distant from hypothalamic-pituitary region. All subjects underwent also ITT. Taking into account appropriate cut-off levels for the two stimuli, GH responses to both tests were highly concordant, but the difference in the GH peak concentrations between GHD and non-GHD irradiated patients was significantly larger for the GHRH + GHRP-6 test than those for the ITT. Some GHD patients based on ITT had a normal GHRH + GHRP-6 test.

 

Based on the studies discussed above, the ITT is preferred to GHRH + ARG and GHRH + GHRP-6 as provocative test for the diagnosis of severe GHD in patients who had cranial irradiation. This recommendation applies to the first years after irradiation only because afterwards all these tests seem reliable and generally concordant. Alternatively, in the first years after irradiation, patients who show normal response GHRH + ARG or GHRH + GHRP-6 would be tested again by ITT to rule out the possibility that GH insufficiency reflecting early hypothalamic impairment is already present.

3.5. Diagnosis of GHD in obese subjects

 

Particular attention has recently been payed to the confounding effect of overweight and obesity on the interpretation of the GH response to provocative tests.

 

Both spontaneous and stimulated GH secretion is negatively associated to BMI [20], [26], [33], [36], [51], [56], [62], [66], [75], [78], [92], [93], [107] and [108]. Particularly, the somatotropic response to all provocative stimuli is negatively correlated to BMI and the GH response in obese subjects is sometimes as impaired as that in hypopituitary patients with severe GHD [20], [33], [36], [51], [56], [66], [74], [75], [77], [78], [92] and [93]. The impairment of GH secretion as a function of overweight and obesity would reflect alterations in the neuroendocrine control of the somatotropic axis and/or metabolic alterations such as hyperinsulinism and elevation of circulating free fatty acids [26]; reduction of GH half-life in obese subjects has also been demonstrated [62] and [107]. Independent of the pathophysiology of GH insufficiency due to weight excess, there is a clinical problem in the interpretation of the GH response to provocative tests in patients suspected of hypopituitarism and severe GHD also taking into account that adult GHD is often associated to weight excess. The cut-off levels of GH response to classical provocative tests have never been validated by BMI level. In fact, it is not enough to include obese subjects in the control group to say that the cut-off levels to provocative tests is defined as function of BMI. By considering obese subjects as normal and, therefore, including them in the populations of control subjects, the cut-off levels were set to avoid the risk of false positive response to a provocative test in patients highly suspected for GHD. However, it should also considered that this approach probably increased the number of false negative responses to the test in lean GHD.

 

For the ITT, the classical cut-off level <3 ?g/L can be considered appropriate based on well known evidence that this level distinguishes normal subjects (including obese) from patients with severe GHD [17] and [61]. However, the cut-off for ITT was 5.1 ?g/L (with 96% of sensitivity and 92% of specificity) in the study by Biller et al. [17] who included obese subjects in the control population. On the other hand, 5 and 3 ?g/L represented the third and first centile limits of the GH response in normal lean subjects in other studies [7] and [61].

 

These slight discrepancies may well reflect variations due to different assays. However, regarding ITT, one should consider that GH peak response below 5 ?g/L is indicative of severe GHD. There are no normative data by BMI for the glucagon or arginine tests.

 

On the other hand, the normative data by BMI of the GH response to GHRH + arginine have been clearly defined. It was first proposed that 9 ?g/L represents the first centile limit of the GH response to GHRH + arginine in normal lean subjects and that a GH peak response below this cut-off in a patient suspected for GHD should be considered as definite evidence of severe GHD in adults [7], [11] and [47]. However, it had been already demonstrated that the GH response to this stimulus is negatively associated to BMI [51], [75], [78] and [92] and this has further confirmed by more recent studies [20] and [93]. This evidence well explains the reason why the cut-off of GH response to GHRH + arginine was defined as 4.1 ?g/L (with 95% and 91% of sensitivity and specificity, respectively) by Biller et al. who again included considerable number of obese subjects in the control group [17]. This cut-off is indeed fully appropriate for the diagnosis of severe GHD in obese adults as shown by the more recent study by Corneli et al. [36]. This study evaluated the GH responses to the GHRH?ARG test in 322 patients with organic hypothalamic-pituitary disease and in 318 control subjects. Patients were grouped on the basis of the number of pituitary hormone deficits, except for GH deficiency: (a) patients with total pituitary hormone deficit (TPHD); and ( B) patients without or with no more than two pituitary hormone deficits (PHD). Both patients and control subjects were divided into three subgroups according to body mass index (BMI): Lean (BMI < 25 kg/m2); overweight (BMI > 25 but <30 kg/m2) and obese (BMI > 30 kg/m2). TPHD patients were assumed to be GH deficient, whereas PHD patients may include subjects with either normal or impaired GH secretion. The statistical analysis was carried out by the ROC curve analysis. The diagnostic cut-off points were calculated for lean, overweight and obese subjects to provide optimal separation of GH-deficient patients and control subjects according to two criteria: (1) a balance between high sensitivity and high specificity; and (2) to provide the highest pair of sensitivity/specificity values for GH deficiency. In the lean population, the best pair of values, with highest sensitivity as 98.7% and highest specificity as 83.7%, was found using a peak GH cut-off point of 11.5 ?g/L. In the overweight population, the best pair of values, 96.7 and 75.5%, respectively, was found using a peak GH cut-off point of 8.0 ?g/L. In the obese population, the best pair of values, 93.5 and 78.3%, respectively, was found using a peak GH cut-off point of 4.2 ?g/L. Applying the above mentioned cut-off points, among PHD patients it was found that 80 subjects (72%) were GHD whereas 31 (28%) had normal GH secretion.

 

Thus, this study once again confirmed that this test is reliable for the diagnosis of adult GHD but emphasized the need that cut-off levels are defined by BMI. Indeed, GH peak cut-off <4.2 ?g/L is appropriate for obese subjects (as demonstrated by Corneli and Biller as well); however, severe GHD is also demonstrated in overweight adults (>25 and <30 BMI) by a GH peak <8 ?g/L and in lean adults by a GH peak <11.5 ?g/L. It is mandatory that cut-offs are considered by BMI in order to avoid false positive responses in obese subjects but also false negative responses in overweight and lean patients.

 

In agreement with the data defining the cut-off limits of GH response to GHRH + ARG by BMI, it has been demonstrated by Kelestimur et al. [66] that the cut-off levelof GH peak below which severe GHD is demonstrated by GHRH + GHRP-6 tests is 5 ?g/L

3.6. Diagnosis of GHD in the transition period adolescent-to-young adult

 

A consensus statements on the management of the GH-treated adolescent in the transition to adult care were recently produced by the European Society for Paediatric Endocrinology in collaboration with the GRS [27] as result of a meeting in Manchester, UK in 2003.

 

The definition of transition was the following:

 

Transition refers to a broad set of physical and psychosocial changes, arbitrarily defined as starting in late puberty and ending with full adult maturation. This usually implies a period from mid to late teens until 6?7 years after achievement of final height. The aims of management in the transition period for the GH-treated adolescent include the following: (a) Re-assessment of aetiology and disease-specific management; ( B) re-assessment of the GH treatment regimen to mimic the diminishing production of endogenous GH secretion; ? achievement of full adult somatic development including lean body mass and bone mineral accrual; (d) completion of pubertal, sexual and reproductive maturation; (e) reduction of metabolic and cardiovascular risks; (f) attainment of adult psychosocial development; and (g) education to ensure that patients have an understanding of their disease to develop autonomy in health care decision making.

 

From the diagnostic point of view, the most important statements of the guidelines are reported below and are followed by comments and suggestions for amendments.

 

Re-assessment of pituitary status

 

GH secretion and insulin-like growth factor-I (IGF-I) levels reach a maximum at mid to late puberty and subsequently decline. This decline is rapid until the mid 20s. The GH replacement strategy differs in childhood from that adopted in adult life: In childhood all degrees of GHD are considered for replacement whereas in adult life only patients with severe GHD are currently treated. Therefore, there is a requirement for re-evaluation of the diagnosis when the major paediatric goals of treatment have been reached. Thus, in adolescents with GHD, treatment should be stopped for re-evaluation of the diagnosis when growth and pubertal development are considered to be complete. All patients require re-evaluation of pituitary function during transition (with the only exception being those with severe congenital or acquired panhypopituitarism). The interval between the re-evaluation and the discontinuation of GH should not be less than one month.

 

GH reserve is assessed by measurement of a serum IGF-I concentration and/or a GH stimulation test.

 

The tests currently recommended are the insulin tolerance test (ITT) with the arginine or glucagon tests as alternatives (1). The GH-releasing hormone (GHRH)?arginine test may be unreliable in patients with suspected hypothalamic disease. The GHRH and clonidine tests alone are not useful.

 

The extent of GH?IGF-I re-evaluation depends on the a priori likelihood of profound GHD. Thus we propose the definition of two groups of patients:

 

(a) High likelihood ? those with severe GHD in childhood with or without two or three additional hormone deficits, which may be due to a defined genetic cause, those with severe GHD due to structural hypothalamic ?pituitary abnormalities, central nervous system (CNS) tumours or patients having received high-dose cranial irradiation.

 

( B) Low likelihood ? the remaining patients, including those with idiopathic GHD, either isolated or with one additional hormone deficit.

 

In patients with a high likelihood of persistent GHD, an IGF-I value < -2 SDS off GH treatment for at least 4 weeks should be considered sufficient evidence of profound GHD. If the IGF-I is >-2 SDS, a GH provocation test should be performed. If this shows a low GH response, the diagnosis of GHD is reconfirmed. If the peak GH is above the appropriate cut-off value, the diagnosis should be reconsidered.

 

Patients with a lower likelihood of retesting GH deficient should have an IGF-I measurement and one GH provocation test. If both are low, the diagnosis of GHD is reconfirmed. If both are normal, the patient can be discharged unless they are at risk of evolving endocrinopathy, such as those who received prior CNS irradiation. If the tests are discordant, the patient should be followed-up.

 

Severe GHD in adults has been defined as a peak GH response <3 ?g/L in response to an ITT and is an accepted criterion for GH replacement therapy in adults. However, this definition is likely to be too conservative in the transition period. In normal children, the most exuberant GH response to a stimulation test occurs in late puberty with GH levels inevitably exceeding 5 ?g/L. Thus we propose the criteria for severe GHD in the transition period to be <5 ?g/L in response to a GH stimulation test.

 

On re-evaluation of the population of adolescents who received GH replacement for childhood GHD, a proportion will not be severely GH deficient but will fail to attain normal GH status (peak GH level < 10 ?g/L but >5?g/L). It is apparent that a significant number of these patients will be reluctant to comply with long-term follow-up. However, the possibility of an evolving endocrinopathy justifies continued surveillance. Before testing, adequate hormone replacement is required. Full pituitary function testing is not required in patients already diagnosed and substituted for complete combined pituitary deficiency. Oral oestrogen may decrease IGF-I levels. This should be taken into consideration. However, the effect of oestrogen on the efficacy of diagnosing GHD in the transition patient has not been evaluated. In other cases basal testing should be performed regularly, particularly in patients at high risk for evolving hormonal deficits, i.e. genetic defects, hypothalamic-pituitary malformations, post-CNS tumour surgery, infiltrating tumours, autoimmune diseases and irradiated patients.

 

Any patient with severe GHD should have cranial and pituitary magnetic resonance imaging (MRI) evaluated according to a standardised protocol, including measurements of pituitary height and search for CNS malformations. Many will have had MRI at diagnosis in childhood, and this does not need repeating.

 

It has to be emphasized that these guidelines for the transition adolescent already provide some diagnostic value to the measurement of total IGF-I levels in agreement with what has been proposed for adults (see above).

 

On the other hand, the statements about the provocative tests and the appropriate cut-off limits of reference for the diagnosis in patients at either high or low likelihood who have non diagnostic IGF-I levels would be appropriately amended taking into account the following points.

 

It seems fully acceptable that, like in the adult, the ITT is a reference provocative test of reference. Also, it would be reasonable that, among classical provocative stimuli, glucagon is considered a good alternative to the ITT.

 

The cut-off level of 5 ?g/L below which severe GHD is diagnosed in the transition adolescent was, however, an arbitrary assumption reflecting the lack of data. More recently, normative values for ITT in the transition adolescents have been defined.

 

Maghnie et al. [79] selected 26 patients for re-evaluation of the GH response to ITT by considering one of the following two criteria for the diagnosis of permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies) or the magnetic resonance imaging identification of structural hypothalamic?pituitary abnormalities. Eight subjects had isolated GHD and 18 had multiple pituitary hormone deficits. Normative data for peak GH were obtained after ITT in 39 healthy subjects. Mean peak GH response to ITT was clearly lower in the 26 patients than in the controls. The diagnostic accuracy of a peak GH response of 6.1 ?g/L showed 96% sensitivity with 100% specificity. In the same study, the reference range for IGF-I was calculated using normative data from 117 healthy individuals. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of -1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I < 2.0 SDS showed a sensitivity of 62%. Based on these findings, the authors stated the cut-off value of the peak GH response to ITT of less than 3 ?g/L or 5 ?g/L is a too restrictive for the diagnosis of permanent GHD in the transition period. It was proposed that permanent GHD is demonstrated by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic?pituitary abnormalities.

 

Normative data for the GH response to glucagon and arginine alone have not been defined yet and this further point toward ITT as classical provocative test of reference for retesting the transition adolescent with childhood-onset GHD.

 

The normative data for the GH response to GHRH + ARG have been defined in children where a GH peak below the cut-off limit of 20 ?g/L had been demonstrated capable of defining GHD due to pituitary pathogenesis [48]. The definition of normative cut-off of the GH response to GHRH + ARG in the transition age by using the ROC curve analysis is currently being performed.

4. 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 childhood-onset, severe GHD or with multiple pituitary hormone deficits acquired in adulthood) can be considered to have severe GHD; these patients would not require provocative tests. We suggest that normal IGF-I levels do not rule out severe GHD and, therefore, these patients must be investigated by provocative tests.

 

? The ITT remains a test of reference but it is 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 (i.e. GHRP-6) have well defined cut-off limits, are reproducible and able to distinguish between normal and GHD subjects.

 

(d) It is recommended that, given the confounding effect of overweight or obesity on the interpretation of the GH response to provocative tests, cut-off levels of GH response are appropriate to lean, overweight and obese subjects in order to avoid false positive diagnosis in obese adults, but also false negative diagnosis in lean GHD adults.

 

(e) It is recognized that normative values of GH response to provocative tests may depend on age and this is of major relevance during the transition period. Data for normative cut-off levels of GH response to ITT are now available.

 

References

 

[1] R. Abs, A.F. Mattsson, B.A. Bengtsson, U. Feldt-Rasmussen, M.I. Goth, M. Koltowska-Haggstrom, J.P. Monson, J. Verhelst, P. Wilton and KIMS Study Group, Isolated growth hormone (GH) deficiency in adult patients: Baseline clinical characteristics and responses to GH replacement in comparison with hypopituitary patients. A sub-analysis of the KIMS database, Growth Horm. IGF Res. 15 (5) (2005), pp. 349?359 October. Abstract | Full Text + Links | PDF (171 K) | View Record in Scopus | Cited By in Scopus (10)

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I'm glad that adult Growth Hormone deficiency is becoming more widely known, and recognized as something that needs treated. It still has a long way to go. When the pharmacy called me, where my Genotropin comes from, they said, "We have a prescription for your daughter, Gracie. I guess she is GH deficient." I started laughing and said, "I'm Gracie!" They acted a bit baffled and was quiet for a second and said, "Oh.... well.... we have orders for you then." I figured they would be more famililar with adult GH deficiency, since they are the ones dispensing the drug. Apparently, they are not.

 

Gracie

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I wanted to make sure I read this right-

 

So, according to that study, someone who has a BMI over 30 (considered obese) has a cut-off for GHD of 4.2 in the arginine/ghrh test. Where it's a cut-off of 11.5 for those who are lean and 8 for those who are overweight (but under 30 in BMI).

 

Is this correct? It doesn't matter that you have other hormone deficiencies, it's all hinges on your BMI?

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This really interested me in confirming me having childhood growth hormone deficiency. I know that I still could have cp, but the part,

 

"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."

 

 

That could be me? I don't know.. it is just a thought. I just want to prove somehow that I may not have cerebral palsy since there is no real chemical test for the condition. If I walk a certain way I have an illness.

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