Body Composition and Bone Mineral Density in Adolescents with Partial Growth Hormone Deficiency

Annemieke M. Boot

Division of Endocrinology, Department of Pediatrics Erasmus MC/Sophia Children’s Hospital Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Annemieke M. Boot, M.D., Ph.D., Division of Endocrinology, Erasmus MC/Sophia Children’s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.

The major role of GH during childhood is to promote longitudinal bone growth. Besides growth, GH affects body composition, bone mineralization, and lipid metabolism. GH deficiency (GHD) in children, as well as in adults, is associated with increased fat mass and decreased lean body mass (mainly muscles) and bone mass (1, 2). It has been reported that during GH therapy of children with GHD fat mass normalized within 6 months (1). Height, lean tissue mass, and bone mass increased during GH treatment but were still significantly lower than normal after 6 yr of treatment (3). The tallest reported mean final height of GH-deficient children treated with recombinant human GH was -0.7 SD below mean height (4). Early diagnosis and sufficient treatment improve final height and may also improve normalization of lean body mass and bone mass, by permitting catch-up growth. At final height, patients are retested for GHD using the diagnostic criteria for GHD in adults, because a substantial proportion of patients, especially those with idiopathic isolated GHD, treated with GH during childhood show a normal GH status at final height (5). The criteria for GHD in adults differ specifically from children with respect to the cut-off peak GH level during the GH stimulation test. Rates of GH secretion reach maximum levels by mid-puberty; thereafter, GH secretion declines rapidly with age (5). Therefore, the peak GH levels in the stimulation test are lower in adults than in children. Most agree that a GH peak response <3 µg/liter in the insulin tolerance test (ITT) is diagnostic for GHD in adults vs. 5–10 µg/liter in children (5). A consensus is reached to treat GH-deficient adults with GH to prevent long-term consequences, such as increased central adiposity, decreased lean body mass, osteoporosis, enhanced cardiovascular risk, and reduced quality of life. Indeed, recent studies have shown that adolescents with childhood onset GHD who continued to be severely GH deficient lost lean body mass when GH was discontinued, whereas healthy adolescents of similar ages demonstrated increased lean body mass and muscle strength (6). Another study reported a significant decrease in muscle strength and an increase in fat mass in adolescent patients after cessation of GH (7). It is noteworthy that lumbar spine bone mineral density (BMD), corrected for bone area, was significantly reduced at final height in treated patients with childhood onset GHD, but lumbar spine BMD corrected for bone volume did not differ from normal (8). This may be explained by the fact that areal BMD is dependent on bone size and, therefore, related to height, whereas volumetric BMD is not. In most studies, final height of the treated GH-deficient patients is less than that of the control population. The prevalence of fractures did not differ between patients and controls (8). Lumbar spine BMD and total body bone mineral content continued to build up in patients with childhood onset GHD who proceeded with GH treatment at completion of linear growth but remained stable in patients who discontinued GH (9). These studies show that complete muscle and bone maturation is reached at a later stage than final height. Lean body mass and bone mass continue to increase for about 2–3 yr after epiphyseal fusion (3, 5). Bone mass is associated with muscle mass, and, therefore, increase of muscle mass is of importance in the attainment of peak bone mass. Bone mass later in life is determined by peak bone mass acquired during adolescence and the subsequent rate of bone loss. Osteoporosis is a major public health problem involving postmenopausal women and aging individuals, and low peak bone mass results in a higher risk of osteoporosis. Therefore, the acquisition of adequate bone mass during childhood is essential to prevent osteoporosis later in life.

In addition to the risk of osteoporosis, an increased chance of cardiovascular morbidity and mortality is observed in adults with GHD because of high fat mass and adverse changes in lipid biochemistry. Studies showed that adults with severe GHD were both physically and psychologically less healthy than their age-matched peers and benefited from GH treatment (5).

Now, it is recommended that patients with severe GHD should continue GH treatment at adult dose. However, it is still unresolved whether during the transition period the pediatric dose or the adult dose should be prescribed (5). Serum IGF-I measurements may be used to avoid overreplacement, keeping values in the age- and sex-related normal range. Serum IGF-I levels like rates of GH secretion decline with age once puberty is complete, and they vary with gender (5). In the transition of GH therapy into adult life, the pediatric dose may gradually be tapered down guided by IGF-I levels. Another approach would be to continue GH at the pediatric dose until the completion of somatic development to allow maximal accrual of bone and muscle mass.

In this issue of JCEM, Tauber et al. (10) raise the issue of the necessity to follow up adolescents with the diagnosis of partial GHD. Retesting at final height was performed with the clonidine test in the majority of the patients. The clonidine test is less useful in adults than in children, because it gives a less profound release of GH than the ITT (11). The Growth Hormone Research Society recommends that after the attainment of final height, retesting of the patient’s GH–IGF-I axis should be performed according to the adult GHD diagnostic criteria. The ITT, or alternatively the arginine plus GHRH test, is advised to be used after an interval of no GH therapy for at least 1 month (11). In the study by Tauber et al. (10), after 1 yr off GH treatment the ITT was used with a cut-off level of 11.8 µg/liter or 20 mU/liter for the diagnosis of partial GHD. Patients with organic or severe GHD (peak, <3 µg/liter) were excluded. Surprisingly one group of patients (n = 9) had a normal GH response after clonidine testing but an insufficient GH response in the ITT 1 yr later. Follow-up of these patients is recommended. The relatively low specificity of the pharmacological provocative tests is a reason that the Growth Hormone Research Society recommends that in idiopathic isolated GHD two biochemical tests of GH status should be abnormal to establish the diagnosis of isolated GHD in adults. In patients with multiple pituitary hormone deficits, a single provocative test is sufficient (11).

Surprisingly, the patients with childhood onset partial GHD had normal IGF-I and IGF-binding protein 3 (IGFBP-3) values compared with American reference values (obtained from Diagnostic System Laboratories, Webster, TX) and compared with patients tested as GH sufficient. Unfortunately, in the study by Tauber et al. (10), no age- and sex-adjusted normal ranges of IGF-I and IGFBP-3 were available for the investigated population. Nevertheless, in adults, a normal serum IGF-I does not exclude the diagnosis of GHD (11). However, it has been reported that young adults with childhood onset GHD have lower IGF-I and IGFBP-3 serum concentrations than patients with adult onset GHD, and a significant correlation has been observed between IGF-I concentration and lean body mass in these patients (12).

The adolescents who were diagnosed as partial GH deficient during retesting at final height had higher fat mass and lower lean body mass at completion of GH treatment and 1 year after cessation of GH treatment, compared with those who tested normal. After discontinuation of treatment, a small increase in fat mass and a significant decrease in lean tissue mass was seen in the partial GH-deficient group, resembling the changes seen in adolescents with severe GHD who stop GH therapy (7). No change in total body BMD SD score and lipid metabolism was observed, which might be because of the fact that the follow-up time was too short. However, changes in lumbar spine BMD may be detected earlier than changes in total body BMD, because lumbar spine consists mainly of trabecular bone with higher bone turnover than cortical bone. Also, changes in biochemical markers of bone metabolism may occur earlier than differences in BMD. The mechanism of osteopenia observed in GHD is likely related to reduced bone remodeling activity (5). This is demonstrated in a study of GH-deficient adolescents that showed a significant decrease in markers of bone turnover 1 yr after discontinuation of GH therapy (13). Increases of markers of bone turnover are observed as early as a few months after the onset of GH treatment in GH-deficient patients (5). In a longitudinal study of severe GH-deficient adolescents, low-density lipoprotein cholesterol and triglyceride levels and the ratio between total cholesterol and high-density lipoprotein cholesterol increased 6 months after GH withdrawal (14). In partial GH-deficient patients, however, it may take longer before changes in the lipid profile become apparent.

The study by Tauber et al. (10) concerns an interesting subject of changes in body composition in adolescents with partial GHD after discontinuation of GH. A weakness of the study is the lack of appropriate reference values, which are essential to evaluate whether and how much body composition is different from normal. Body composition may differ between populations because of differences in genetically predisposed height, diet, and racial influences. Longer follow-up with evaluation of body composition, BMD, and lipid metabolism is needed to know whether adolescents with partial GHD develop a partial adult GHD syndrome, which may be less extreme than in severe GH-deficient patients. If such a mild GHD syndrome exists, the question arises whether these patients may benefit from GH treatment.

Footnotes

Abbreviations: BMD, Bone mineral density; GHD, GH deficiency; IGFBP-3, IGF-binding protein 3; ITT, insulin tolerance test.

Received September 18, 2003.

Accepted September 18, 2003.

References

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