Why Retest Young Adults with Childhood-Onset Growth Hormone Deficiency?

H. de Boer and E. A. van der Veen

Address all correspondence and requests for reprints to: Dr. Hans de Boer, Spaarne Ziekenhuis Haarlem, P.O. Box 1644, 2003 BR Haarlem, The Netherlands.


    Introduction
 Top
 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 
In the past decade it has become increasingly clear that growth hormone deficiency (GHD) has clinical implications for adult man. The main characteristics of the adult GHD syndrome are an increased subcutaneous and visceral fat mass, a reduced extracellular fluid volume, a subnormal muscle mass, a low bone density, a reduced cardiac performance, moderately elevated serum low density lipoprotein (LDL) cholesterol levels, reduced physical performance, impaired cognitive function, and reduced well-being (1, 2). Many of these abnormalities are at least partially reversible with GH replacement started in adult life. Based on these observations the concept is emerging that it might be advisable not to stop GH replacement therapy in GHD adolescents who have reached their final height.

The main objective of the present review is to evaluate whether current evidence is sufficiently strong to support a policy that proposes continuation of GH treatment in young adults with a diagnosis of GHD in childhood to prevent the development of the adult GHD syndrome in these patients.


    The Consequences of Stopping GH Treatment
 Top
 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 
The aim of continuation of GH replacement in adulthood is to prevent GHD-related morbidity without introducing new risks associated with the institution of GH treatment. Treatment strategies aimed at prevention of GHD-related morbidity are indicated if the long-term consequences of adult GHD are known to be severe and if the efficacy of treatment has been firmly established. The consequences of prolonged GH depletion in adults have been evaluated in patients with adult-onset GHD (AO-GHD) as well as in adults with childhood-onset GHD (CO-GHD). Although both patient groups show marked similarities, they are not entirely comparable. Attanasio et al. (3) recently demonstrated that adults with CO-GHD (n = 74) had lower serum insulin-like growth factor I (IGF-I) levels, lower body height, more severe decrease in lean body mass, less severe increase in total cholesterol levels, higher HDL-cholesterol levels, and higher osteocalcin levels, and that they scored better on quality-of-life assessments than patients with AO-GHD. The logical consequence of these observations is that an assessment of the severity of the consequences of GHD for adults with CO-GHD will lose accuracy if the analysis includes data obtained from patients with AO-GHD.

The main findings of controlled studies performed in adults with CO-GHD are summarized in Table 1Go (see references 4–11). They provide cross-sectional data of patients with severe GHD who have been without GH for a mean period of approximately 8 yr. The first impression is that abnormalities of this degree should be avoided if possible. However, it is uncertain whether the current generation of GHD adolescents will develop abnormalities of a similar degree once their GH treatment is discontinued. The observations on body composition and on physical and psychological performance are not exclusively the result of withdrawing GH treatment at final height, but they also reflect the consequences of suboptimal GH treatment during childhood and adolescence. According to current standards, most patients who were included in these studies received suboptimal GH treatment during childhood because of the limited supply of pituitary-derived GH. The effects on final height were poor. Mean final height was approximately 2 SD below the normal mean. It is most likely that the treatment regimens during childhood were also insufficient to normalize body composition and physical performance, and that discontinuation of GH treatment at final height only caused a further deterioration of preexisting abnormalities. The relative impacts of suboptimal treatment during childhood and the discontinuation of GH treatment in early adulthood are not known.


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Table 1. Results of controlled studies in adults with a diagnosis of childhood-onset GHD

 
There are currently only two uncontrolled, longitudinal studies showing that discontinuation of GH treatment does have deleterious effects on body composition (12, 13). In a study of 8 patients (7 males, 1 female) with a peak GH response less than 5 µg/L, Rutherford et al. (12) showed that discontinuation of GH treatment for 1 yr was associated with an increase in body fat from 19.5 \ 8.6% to 24.1 \ 9.5%, assessed by measurement of skinfold thickness. Muscle mass and muscle strength decreased by approximately 5% during this period. Colle et al. (13) studied 5 male adolescents and found that body fat increased by 4.1 \ 2.2 kg in the three months following discontinuation of GH treatment. This observation was based on bioimpedance analysis, a method that tends to overestimate changes in body fat in GHD patients (2). Controlled or uncontrolled longitudinal studies demonstrating that discontinuation of GH replacement has deleterious effects on cardiac muscle structure and function or that it adversely affects the build-up and maintenance of bone mass are currently not available. In a recent study on bone density in 33 young adults with CO-GHD we found no significant change in bone mineral density (BMD) during a mean follow-up of 2 yr (our unpublished data). This is in agreement with the findings of Kaufman et al. (6) who studied BMD in 19 GHD patients for a period of 10–15 months.

The current generation of GHD adolescents is expected to start adult life in better condition because they have received more optimal treatment during childhood. Nowadays, treatment is started at an earlier age, and GH replacement doses are much higher than previously employed. Both measures serve to improve final height. With these higher doses of GH a normalization of bone density can be achieved (14). It remains to be demonstrated whether the recent improvements of GH treatment during childhood and adolescence will also lead to a normalization of body fat, muscle mass, cardiac function, and physical performance at final height.

In conclusion, although the existence of the adult GHD syndrome is definitely established, it is conceivable that the clinical picture in the coming generation of adults with CO-GHD may be somewhat different and less severe than demonstrated in patients who received suboptimal treatment during childhood and adolescence.


    Who Is at Risk to Develop the Adult GHD Syndrome?
 Top
 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 
Identification of the risk factors that determine the likelihood of developing the adult GHD syndrome is an essential step in the process of selecting the patients that may or may not benefit from continuation of GH treatment. Table 2Go summarizes the characteristics of adults with CO-GHD who were included in studies that evaluated the consequences of GHD or the efficacy of GH treatment (3–27). It is worth noting that 85–100% of the patients had a peak GH response less than 5 µg/L, and that the number of women who were studied was extremely small. Thus, any conclusion or prediction made on the basis of these studies is only valid for male patients with severe GHD. So far, there are no data supporting the conclusion that patients with partial GHD, i.e. those with a peak GH response of 5–10 µg/L, are at risk to develop the adult GHD syndrome, nor has it been shown that the consequences of GHD are of similar severity in men and in women.


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Table 2. Characteristics of adults with childhood-onset GHD in A) controlled and uncontrolled studies evaluating the consequences of GHD, and in B) studies evaluating the effects of GH treatment

 

    The Efficacy of GH Treatment
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 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 
In adults with CO-GHD who have developed the adult GHD syndrome, GH treatment reduces body fat (4, 24), increases muscle mass (5, 24) and bone density (21, 23, 26), improves cardiac structure and function (9), physical performance (24), and cognitive function (28), and may lower serum LDL cholesterol (20). The latter only occurs in patients initially presenting with an elevated LDL cholesterol level. As observed previously, the effects of treatment have mainly been studied in men who were severely GHD and who had discontinued previous GH treatment for short stature for approximately 8 yr. The observed GH-induced changes in body composition were large. Subcutaneous fat mass decreased by 27% (95% CI: 22–32%) and intraabdominal fat mass by 47% (95% CI: 36–57%) (4). Anthropometric measurements indicated that muscle mass increased by 20–25% after 1 yr of GH treatment (5). In 6 patients studied for 30 months, lumbar spine bone mineral content increased by 7% and forearm bone mineral content by 10% (23). After 3 yr of GH treatment the increase in exercise capacity was approximately 40% (24). The GH-induced decline in LDL cholesterol amounted to approximately 10% (20). The overall conclusion is that the changes induced by GH treatment are sufficiently large to consider this mode of treatment beneficial and clinically relevant in CO-GHD men who have developed the adult GHD syndrome. Moreover, results of long-term treatment are encouraging because they indicate that improvements achieved during short-term treatment are sustained (24). Whether treatment will be equally effective in women with CO-GHD remains to be demonstrated. In AO-GHD adults there is some evidence emerging that women are less responsive to GH treatment than men (29, 30, 31).


    Why Retest the GH-Axis in Young Adults with CO-GHD?
 Top
 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 
Obviously, the objective of retesting CO-GHD adults is to confirm the diagnosis of GHD once they have reached adulthood to identify the patients who may be at risk of developing the adult GHD syndrome. One of the main reasons to strongly advocate retesting is that a former diagnosis of GHD in childhood is insufficient evidence to conclude that a patient will be GHD for life.

Cacciari et al. (32) clearly demonstrated this when they retested a large group of children with isolated GHD (IGHD) 4 weeks after interruption of GH replacement therapy. In their first study 13 out of 53 children (24.5%) had a normalization of GH peak responses to 2 provocative tests. In a subsequent, more extensive study, 44 out of 132 children (28.9%) had a normalization of the GH response (33). Normalization of GH responsiveness is also frequently observed if retesting is performed in adulthood. Longobardi et al. (34) retested 69 adults with childhood-onset GHD of varying etiology using a combination of GHRH plus pyridostigmine (GHRH PD). Thirty patients (43%) had a normal GH response, defined as peak GH response greater than 10 µg/L. A subsequent insulin tolerance test (ITT) revealed that 3 patients with a normal response to GHRH PD had a subnormal response to ITT, whereas all patients who had a subnormal response to GHRH PD also had a subnormal response to ITT. Thus, if the ITT is used as the gold standard, 27 out of 69 (40%) patients had a normalization of GH responsiveness. This is in close agreement with findings in other studies. Table 3Go summarizes the prevalence of normalization of GH responsiveness in CO-GHD adults, observed in studies using either the ITT or the arginine stimulation test (AST) (12, 35, 36, 37). The patients are categorized according to the etiology of GHD. Normalization of GH secretion was observed in 35% of the patients with IGHD. As expected, it was rare in patients with extensive damage in the hypothalamic-pituitary area. It occurred in 11% of the patients with multiple pituitary hormone deficiencies (MPHD), in 3% of the patients with irradiation-induced GHD, and in none of the patients who had been treated for craniopharyngioma. The chance of a normal GH response upon retesting in adulthood is much higher in patients with a previous diagnosis of partial GHD (GH peak response 5–10 µg/L) than in those with complete GHD (GH peak response <5 µg/L). In a study of 131 patients with a diagnosis of GHD in childhood, normalization of GH responsiveness was observed in 36% of the patients with a previous diagnosis of complete GHD and in as much as 71% of the patients with previously established partial GHD (38). The likelihood of normalization of GH responsiveness is not different for men and women, and it is independent of whether the previous diagnosis of GHD was established before or during puberty (38).


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Table 3. Normalization of GH responsiveness in CO-GHD patients upon retesting in adulthood: summary of studies using the insulin tolerance test or the arginine stimulation test

 
Another reason to advocate retesting is that the biochemical criteria for a diagnosis of GHD in adults are different from those used to accept the diagnosis of GHD in children. Although a consensus on the diagnosis of GHD in adulthood has not yet been reached, most will agree that a GH peak response less than 5 µg/L is diagnostic (39). This cut-off limit, also represents the upper limit of the GH responses observed in the majority of patients who have acquired the abnormalities characteristic of the adult GHD syndrome (Tables 1Go and 2Go). The practical consequence of using the 5 µg/L limit is that only a proportion of the adolescents who are now receiving GH treatment for short stature will be eligible for continuation of GH treatment in adulthood. Nicolson et al. (37) evaluated the prevalence of severe GHD in adults who received GH replacement in childhood. Using the insulin or arginine test for reevaluation of GH secretion in adulthood, they found that 53 of 88 patients (60%) had a peak GH response less than 4.5 µg/L (25). In Tauber’s study (38), only 30 out of 131 patients (23%) had a peak GH response less than 5 µg/L after retesting with clonidine betazolol. If we combine these data, approximately 60% of the children with a former diagnosis of GHD will not be eligible for continuation of GH treatment in adulthood if a cut-off limit of 5 µg/L is used.


    The Preferred Pharmacological GH Stimulation Test in Adulthood
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 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 
In the past 30 yr a large number of physiological and pharmacological GH stimulation tests have been developed to evaluate the integrity of the GH-axis. In children, the most frequently used pharmacological stimuli are insulin, arginine, levo-dopa, clonidine, and glucagon (40). In adults the GHRH test is also frequently employed (2, 34). The limitations of each test are well known (2, 40). The recent statement that "it is simplistic and unrealistic to believe that a single biochemical assay can be relied upon to establish a diagnosis of GHD" (41) deserves a prominent place in the office of clinicians involved with GH treatment. However, until a more appropriate diagnostic protocol has been developed and validated, we have to live with the limitations of the conventional methodology for establishing a diagnosis of GHD. For research purposes as well as for clinical decision making it would be better if the number of provocative tests used at various centers were reduced to a minimum and if the biochemical approach to diagnose GHD was thoroughly standardized worldwide. A comparison of study results is only possible if selection and categorization of patients is based on a similar test procedure. We strongly advocate inclusion of the ITT in all diagnostic procedures that aim to establish a diagnosis of GHD in adults. In some pediatric centers the ITT has fallen from favor because of the chance of adverse effects resulting from hypoglycemia or overly vigorous correction of hypoglycemia (42). In adults, however, this test appears to be a safe procedure when performed in an experienced endocrine unit with adequate supervision. Hoffman (43) summarized the ITT experience of 3 centers and found that, in 1 out of 443 tests (0.2%), an adverse event had occurred. This one patient had a hypoglycemia-induced seizure and recovered without sequelae. The ITT has a high diagnostic accuracy in adults (39), and it induces a more profound GH release than arginine, glucagon, clonidine, levo-dopa, or exercise (44, 45, 46). A final argument to favor the ITT is that it is one of the most frequently used tests in studies that have evaluated the consequences of GHD in adults. It is debatable which test should be used if the ITT is contraindicated. There are several options, such as the glucagon, the arginine, the levo-dopa, or the GHRH test, but the number of comparative studies is too small to give firm recommendations as to which test is the best alternative for the ITT. The use of the clonidine test is not recommended. In healthy adults it induced peak GH responses that were indistinguishable from placebo (44).

Serum IGF-I and IGFBP-3 measurements are commonly used as additional instruments to evaluate the GH status in childhood. In adults with childhood-onset GHD, the diagnostic value of serum IGF-I and IGFBP-3 measurements is comparable with that in GHD children (3, 47, 48). In patients with adult-onset pituitary disease these markers have limited diagnostic accuracy. Normal levels were found in a large proportion of patients who had a subnormal GH response to ITT (43). A satisfactory explanation for this somewhat surprising observation is lacking.


    Conclusions and Recommendations
 Top
 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 
We strongly advocate retesting of all patients with CO-GHD, preferably by ITT, once they have reached their final height. Retesting serves to identify the patients who have so called transient GHD and who are therefore not at risk to develop the adult GHD syndrome. Patients with a GH response less than 5 µg/L are most likely to develop the adult GHD syndrome if GH treatment is stopped at final height, and this group is expected to benefit substantially from GH treatment in adulthood. The prognosis of patients with a GH response of 5–10 µg/L is not known.

The efficacy of a treatment strategy that aims to prevent the development of the adult GHD syndrome in patients with CO-GHD remains to be demonstrated in placebo-controlled trials. As long as these data are not available it is recommended that all patients with a reduced GH-response be monitored for a period of at least 5 yr, with special emphasis on body composition, serum lipid levels, and physical performance. Parameters that reliably predict how severe the abnormalities will be in due time if GH treatment is stopped, or that reliably predict what the exact benefits are of continuation of GH treatment for an individual patient have not been identified yet. For the present, therefore, it seems most plausible to base the decision of GH treatment in adulthood on developments observed in the patient after discontinuation of GH treatment for short stature. In view of our still limited knowledge it presently appears to be the only reliable approach to demonstrate that a patient may or may not need GH treatment in adult life. An exception should be made for those GHD patients with a low bone mineral density at final height. Continuation of GH treatment is advised until normalization of bone mineral density is achieved.

Received April 9, 1997.

Accepted April 16, 1997.


    References
 Top
 Introduction
 The Consequences of Stopping...
 Who Is at Risk...
 The Efficacy of GH...
 Why Retest the GH-Axis...
 The Preferred Pharmacological GH...
 Conclusions and Recommendations
 References
 

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